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Abstract Background Extracellular ATP–AMP–adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell–derived ATPases in the development and progression of colon cancer. Methods Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. Results We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. Conclusion Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP–adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.

Abstract The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I–MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer.

Abstract Despite the growing use of cochlear implants in deaf patients, there is a lack of data on their knowledge, attitude, and practice (KAP) toward cochlear implants. This study aimed to investigate the KAP toward cochlear implants among deaf patients who received cochlear implants. A web-based cross-sectional study was conducted between August 2022 and December 2022 among deaf patients who had received cochlear implants. A self-administered questionnaire was used to collect demographic characteristics and KAP scores. A total of 526 participants were enrolled; 54.18% were female, 65.40% were above 60 years old, and 61.03% were surveyed at less than 3 years after implantation. The mean knowledge, attitude, and practice scores were 8.15 ± 2.18 (possible range: 0–10), 43.63 ± 6.98 (possible range: 12–60), and 41.11 ± 7.42 (possible range: 11–55), respectively, indicating good knowledge, moderate attitude and practice. Multivariable logistic regression analysis showed that attitude [odd ratio (OR) = 1.24, 95% confidence interval (CI) 1.18–1.29, P

Abstract Stochastic resonance is an essential phenomenon in neurobiology, it is connected to the constructive role of noise in the signals that take place in neuronal tissues, facilitating information communication, memory, etc. Memristive devices are known to be the cornerstone of hardware neuromorphic applications since they correctly mimic biological synapses in many different facets, such as short/long-term plasticity, spike-timing-dependent plasticity, pair-pulse facilitation, etc. Different types of neural networks can be built with circuit architectures based on memristive devices (mostly spiking neural networks and artificial neural networks). In this context, stochastic resonance is a critical issue to analyze in the memristive devices that will allow the fabrication of neuromorphic circuits. We do so here with h-BN based memristive devices from different perspectives. It is found that the devices we have fabricated and measured clearly show stochastic resonance behaviour. Consequently, neuromorphic applications can be developed to account for this effect, that describes a key issue in neurobiology with strong computational implications.

Vaccines are the most effective and feasible way to control pathogen infection. Helminths have been reported to jeopardize the protective immunity mounted by several vaccines. However, there are no experimental data about the effect of helminth infection on the effectiveness of COVID-19 vaccines. Here, a mouse model of trichinosis, a common zoonotic disease worldwide, was used to investigate effects of Trichinella spiralis infection on the RBD protein vaccine of SARS-CoV-2 and the related immunological mechanism, as well as the impact of albendazole (ALB) deworming on the inhibitory effect of the parasite on the vaccination. The results indicated that both the enteric and muscular stages of T. spiralis infection inhibited the vaccine efficacy, evidenced by decreased levels of IgG, IgM, sIgA, and reduced serum neutralizing antibodies, along with suppressed splenic germinal center (GC) B cells in the vaccinated mice. Pre-exposure to trichinosis promoted Th2 and/or Treg immune responses in the immunized mice. Furthermore, ALB treatment could partially reverse the inhibitory effect of T. spiralis infection on the efficiency of the vaccination, accompanied by a restored proportion of splenic GC B cells. Therefore, given the widespread prevalence of helminth infections worldwide, deworming therapy needs to be considered when implementing COVID-19 vaccination strategies.

[This corrects the article DOI: 10.1371/journal.pone.0271231.].

The post-deposition annealing of AlCrN films was conducted in an atmospheric environment for 2 h, with annealing temperatures ranging from 25 to 1000 °C. The microstructure, mechanical, and tribological properties were systematically investigated as a function of the annealing temperature. The results show that the AlN phase in the film began to oxidize at 600 °C, resulting in deterioration of the film's toughness and resistance to plastic deformation. Subsequently, the wear resistance also deteriorated, with the wear rate being nearly 16 times that of the as-deposited film. At 800 °C, the AlN obviously underwent oxidization to form Al2O3. The high temperature annealing promoted the coalescence of Cr on the film surface and caused a reaction with the Al2O3 to form a replacement solid solution of Cr–O–Al, thereby improving the mechanical properties of the annealed films. At the same time, the tribological properties of the films were not significantly deteriorated by annealing at temperatures other than 600 °C, similar to those of the films without any annealing treatment.

Non-noble transition metal oxides (TMOs) are promising catalysts with improved catalytic activity and stability in oxygen evolution reaction (OER). However, the structural complexity of TMO-based electrocatalysts renders the determination of the active sites and OER mechanisms challenging. Here, we demonstrate that the OER activity of Co-doped one-dimensional W18O49 (Co-W18O49) is intrinsically dominated by the surface structure and electronic properties of the octahedral sites and Co–O–W bonds. Compared with RuO2 and W18O49 heterogeneous electrocatalysts, Co-W18O49 exhibits higher turnover frequency, attaining 1.97 s−1 at 500 mV overpotential. The results indicate that Co substitution contributes to the localized charge distribution of the active octahedral sites constructed by the Co–O–W bonds under OER conditions. Here, we determine the mechanism of TMOs for the OER, which may be applied to various other TMOs for OER electrocatalyst design.

Abstract Innate immunity represents one of the main host responses to viral infection.1–3 STING (Stimulator of interferon genes), a crucial immune adapter functioning in host cells, mediates cGAS (Cyclic GMP-AMP Synthase) sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown. In the present study, we discovered that human enterovirus A71 (EV-A71) infection triggered STING activation in a cGAS dependent manner. EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells. However, during EV-A71 infection, cGAS-STING activation was attenuated. EV-A71 proteins were screened and the viral protease 2Apro had the greatest capacity to inhibit cGAS-STING activation. We identified TRAF3 as an important factor during STING activation and as a target of 2Apro. Supplement of TRAF3 rescued cGAS-STING activation suppression by 2Apro. TRAF3 supported STING activation mediated TBK1 phosphorylation. Moreover, we found that 2Apro protease activity was essential for inhibiting STING activation. Furthermore, EV-D68 and CV-A16 infection also triggered STING activation. The viral protease 2Apro from EV-D68 and CV-A16 also had the ability to inhibit STING activation. As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication, blocking EV-A71-mediated STING suppression represents a new anti-viral target.

Objective: To analyze and summarize the experience of single-port robotic-assisted laparoscopic ambulatory surgery (AS) for intraligamental myomectomy. Methods: We analyzed the basic conditions, preoperative myoma assessment, surgical operation, and perioperative management of two patients undergoing robotic-assisted laparoendoscopic single site (R-LESS) intraligamental myomectomy and reviewed in the literature to summarize the initial clinical experience of the robotic AS model. Results: Two cases of R-LESS intraligamental myomectomy were successfully discharged after 29.82 ​h and 25.95 ​h of hospitalization, respectively, with no complications. Conclusion: R-LESS intraligamental myomectomy to achieve AS is safe and feasible. Adequate preoperative myoma evaluation, staging and strict access criteria, combined with current advanced single-port robotic technology and meticulous intraoperative management, and a scientific perioperative Enhanced Recovery After Surgery (ERAS) management process are vital factors to enable AS for intraligamental myomectomy.

Rabies is a zoonotic infectious disease with a high fatality rate. It is caused by a virus in the genus Lyssavirus and is a global public health threat. The rabies virus invades and infects cells mainly via a glycoprotein, which may involve multiple receptors. Neutralizing antibodies against the rabies virus function by blocking the binding of the glycoprotein to a receptor or preventing the membrane fusion process. Vaccination combined with anti-rabies virus neutralizing antibodies is essential for postexposure prophylaxis for category III exposure to the rabies virus. In this review, we discussed the neutralizing epitopes of the rabies virus and the neutralization mechanism of monoclonal antibodies. The neutralizing antibodies that have been commercialized or are under development are also summarized. Our review would provide a basis for the further development of safe and effective broad-spectrum neutralizing antibodies to replace the rabies virus immunoglobulin in rabies post-exposure prophylaxis.

Three or four intramuscular doses of the inactivated human rabies virus vaccines are needed for pre- or post-exposure prophylaxis in humans. This procedure has made a great contribution to prevent human rabies deaths, which bring huge economic burdens in developing countries. Herein, a recombinant adeno-associated virus serotype 9, AAV9-RABVG, harbouring a RABV G gene, was generated to serve as a single dose rabies vaccine candidate. The RABV G protein was stably expressed in the 293T cells infected with AAV9-RABVG. A single dose of 2 × 1011 v.p. of AAV9-RABVG induced robust and long-term positive seroconversions in BALB/c mice with a 100% survival from a lethal RABV challenge. In Cynomolgus Macaques vaccinated with a single dose of 1 × 1013 v.p. of AAV9-RABVG, the titres of rabies VNAs increased remarkably from 2 weeks after immunity, and maintained over 31.525 IU/ml at 52 weeks. More DCs were activated significantly for efficient antigen presentations of RABV G protein, and more B cells were activated to be responsible for antibody responses. Significantly more RABV G specific IFN-γ-secreting CD4+ and CD8+ T cells, and IL-4-secreting CD4+ T cells were activated, and significantly higher levels of IL-2, IFN-γ, IL-4, and IL-10 were secreted to aid immune responses. Overall, the AAV9-RABVG was a single dose rabies vaccine candidate with great promising by inducing robust, long-term humoral responses and both Th1 and Th2 cell-mediated immune responses in mice and non-human primates.

Abstract Traditional Chinese medicine (TCM) injection is the combination of modern pharmaceutical technology and traditional Chinese prescription, which was born in 1941 and played a great role in the backward medical conditions at that time. However, the debate over TCM injections has never stopped due to adverse drug reactions (ADRs). The regulation on TCM injections has been further strengthened since 2017, which has prompted many TCM injections to carry out re-evaluations on quality, safety, efficiency as well as pharmacoeconomics, which made significant changes and progress. This review presented an up-to-date analysis of the types, amounts, and ADRs of TCM injections based on the published data and literature. This review also summarized the potential reasons for the ADRs and re-evaluation strategies. This review will provide some useful clues for TCM injections and their clinical use.

Side-on configuration of O2 on the catalysts conventionally leads to reduction of O2 to water. Here, the authors propose a nitrogen doping strategy with Pauling-type adsorption of O2 for selective electrocatalytic singlet oxygen production.

Abstract Introduction Nalbuphine can relieve patients’ inflammation response after surgery compared to other opioid drugs. However, its molecular mechanism has not been clear. Activation of NF-κB signaling pathway under oxidative stress and inflammation can maintain pain escalation. Methods We firstly investigated the effect of nalbuphine on writhing test and mechanical allodynia using a rat model of inflammatory visceral pain (acetic acid (AA) administrated). Cytokines (including tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, IL-2, and IL-6 in plasma were tested with ELISA technology. Expression levels of TNF-α, IκBα and p-NF-κB p65 at the spinal cord (L3–5) were measured by western blot or RT-qPCR. Results We found that the paw withdrawal threshold (PWT) values of rats were reduced in the model group, while the numbers of writhing, levels of IL-1β, IL-2, IL-6, and TNF-α in plasma, and p-NF-κB protein and its gene expressions in the lumbar spinal cord were up-regulated. Subcutaneously injection of nalbuphine (10 μg/kg) or PDTC (NF-κB inhibitor) attenuated acetic acid-induced inflammatory pain, and this was associated with reversal of up-regulated IL-1β, IL-2, IL-6, and TNF-α in both plasma and spinal cord. Furthermore, acetic acid increased p-NF-κB and TNF-α protein levels in the white matter of the spinal cord, which was attenuated by nalbuphine. These results suggested that nalbuphine can significantly ameliorate inflammatory pain via modulating the expression of NF-κB p65 as well as inflammation factors level in the spinal cord. Conclusion In conclusion, nalbuphine inhibits inflammation through down-regulating NF-κB pathway at the spinal cord in a rat model of inflammatory visceral pain.

Objectives To compare the prognostic values of three lymph node staging systems in renal cell carcinoma (RCC), including the number of positive lymph nodes (NPLN), lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS).Design A retrospective cohort study using data from the Surveillance, Epidemiology and End Results (SEER) database.Setting and participants 1904 patients with pathological N1 RCC, diagnosed from 2004 to 2015 and underwent nephrectomy combined with lymph node dissection, were identified from the SEER database.Primary outcome measure The primary outcome of this study was overall survival (OS). Restricted cubic spline functions and multivariable Cox regression analyses were employed to characterise the associations of OS with NPLN, LNR and LODDS, respectively.Results Data of 1904 eligible RCC patients were extracted from the SEER database. The mortality risks of RCC patients increased with the increasing of NPLN, LNR and LODDS. NPLN (NPLN3 vs NPLN1, HR 1.22, 95% CI 1.05 to 1.43, p=0.001), LNR (LNR3 vs LNR1, HR 1.46, 95% CI 1.28 to 1.67, p

BackgroundChronic orofacial pain is a common and incompletely defined clinical condition. The role of G protein-coupled estrogen receptor 1 (GPER1) as a new estrogen receptor in trunk and visceral pain regulation is well known. Here, we researched the role of GPER1 in the rostral ventral medulla (RVM) during chronic orofacial pain.Methods and ResultsA pain model was established where rats were injected in the temporomandibular joint with complete Freund’s adjuvant (CFA) to simulate chronic orofacial pain. Following this a behavioral test was performed to establish pain threshold and results showed that the rats injected with CFA had abnormal pain in the orofacial regions. Additional Immunostaining and blot analysis indicated that microglia were activated in the RVM and GPER1 and c-Fos were significantly upregulated in the rats. Conversely, when the rats were injected with G15 (a GPER1 inhibitor) the abnormal pain the CFA rats were experiencing was alleviated and microglia activation was prevented. In addition, we found that G15 downregulated the expression of phospholipase C (PLC) and protein kinase C (PKC), inhibited the expression of GluA1, restores aberrant synaptic plasticity and reduces the overexpression of the synapse-associated proteins PSD-95 and syb-2 in the RVM of CFA rats.ConclusionThe findings indicate that GPER1 mediates chronic orofacial pain through modulation of the PLC-PKC signal pathway, sensitization of the RVM region and enhancement of neural plasticity. These results of this study therefore suggest that GPER1 may serve as a potential therapeutic target for chronic orofacial pain.

Abstract Background The characteristics of immune-related long non-coding ribonucleic acids (ir-lncRNAs), regardless of their specific levels, have important implications for the prognosis of patients with bladder cancer. Methods Based on The Cancer Genome Atlas database, original transcript data were analyzed. The ir-lncRNAs were obtained using a coexpression method, and their differentially expressed pairs (DE-ir-lncRNAs) were identified by univariate analysis. The lncRNA pairs were verified using a Lasso regression test. Thereafter, receiver operating characteristic curves were generated, and an optimal risk model was established. The clinical value of the model was verified through the analysis of patient survival rates, clinicopathological characteristics, presence of tumor-infiltrating immune cells, and chemotherapy efficacy evaluation. Results In total, 49 pairs of DE-ir-lncRNAs were identified, of which 21 were included in the Cox regression model. A risk regression model was established on the premise of not involving the specific expression value of the transcripts. Conclusions The method and model used in this study have important clinical predictive value for bladder cancer and other malignant tumors.

Inflammatory bowel diseases (IBDs) have been classified as modern refractory diseases. However, safe, well-tolerated, and effective treatments for IBDs are still lacking. Therefore, there is an urgent need to develop novel therapeutic targets with fewer undesirable adverse reactions. A growing body of research has shown that infection with live helminths or exposure to defined helminth-derived components can downregulate pathogenic inflammation due to their immunoregulatory ability. Here we were to explore the protective role of Schistosoma japonicum eggs on murine experimental colitis caused by trinitrobenzene sulfonic acid (TNBS) and the underlying mechanism. Frequencies of splenic Treg and Th17 cells were detected by flow cytometry. Protein and mRNA expressions of Foxp3 and RORγt were investigated by Western Blot and quantitative real-time polymerase chain reaction (qPCR), respectively. Concentrations of transforming growth factor-beta1 (TGF-β1), interleukin-10 (IL-10) and IL-17A were assessed with ELISA. Expression levels of genes related to glycolipid metabolism were measured with qPCR. The results showed that pre-exposure to S. japonicum eggs contributed to the relief of colitis in the TNBS model, evidenced by improved body weight loss, reversing spleen enlargement and colon shortening, and decreased histology scores. Compared with the TNBS group, the TNBS+Egg group had increased Treg immune response, accompanied by decreased Th17 immune response, leading to the reconstruction of Treg/Th17 balance. In addition, a ratio of Treg/Th17 was correlated negatively with the histological scores in the experiment groups. Furthermore, the regulation of Treg/Th17 balance by S. japonicum eggs was associated with inhibiting the glycolysis pathway and lipogenesis, along with promoting fatty acid oxidation in the TNBS+Egg group. These data indicate that S. japonicum eggs have a protective effect against TNBS-induced colitis, which is related to restoring Treg/Th17 balance and regulating glucose and lipid metabolism.

ObjectivesNew ventilation modes have been proposed to support the perioperative treatment of patients with obesity, but there is a lack of consensus regarding the optimal strategy. Therefore, a network meta-analysis update of 13 ventilation strategies was conducted to determine the optimal mode of mechanical ventilation as a protective ventilation strategy decreases pulmonary atelectasis caused by inflammation.MethodsThe following databases were searched: MEDLINE; Cochrane Library; Embase; CINAHL; Google Scholar; and Web of Science for randomized controlled trials of mechanical ventilation in patients with obesity published up to May 1, 2022.ResultsVolume-controlled ventilation with individualized positive end-expiratory pressure and a recruitment maneuver (VCV+PEEPind+RM) was found to be the most effective strategy for improving ratio of the arterial O2 partial pressure to the inspiratory O2 concentration (PaO2/FiO2), and superior to pressure-controlled ventilation (PCV), volume-controlled ventilation (VCV), volume-controlled ventilation with recruitment maneuver (VCV+RM), volume-controlled ventilation with low positive end-expiratory pressure (VCV+lowPEEP), volume-controlled ventilation with lower positive expiratory end pressure (PEEP) and recruitment maneuver (VCV+lowPEEP+RM), and the mean difference [MD], the 95% confidence intervals [CIs] and [quality of evidence] were: 162.19 [32.94, 291.45] [very low]; 180.74 [59.22, 302.27] [low]; 171.07 [40.60, 301.54] [very low]; 135.14 [36.10, 234.18] [low]; and 139.21 [27.08, 251.34] [very low]. Surface under the cumulative ranking curve (SUCRA) value showed VCV+PEEPind+RM was the best strategy for improving PaO2/FiO2 (SUCRA: 0.963). VCV with high positive PEEP and recruitment maneuver (VCV+highPEEP+RM) was more effective in decreasing postoperative pulmonary atelectasis than the VCV+lowPEEP+RM strategy. It was found that volume-controlled ventilation with high positive expiratory end pressure (VCV+highPEEP), risk ratio [RR] [95% CIs] and [quality of evidence], 0.56 [0.38, 0.81] [moderate], 0.56 [0.34, 0.92] [moderate]. SUCRA value ranked VCV+highPEEP+RM the best strategy for improving postoperative pulmonary atelectasis intervention (SUCRA: 0.933). It should be noted that the quality of evidence was in all cases very low or only moderate.ConclusionsThis research suggests that VCV+PEEPind+RM is the optimal ventilation strategy for patients with obesity and is more effective in increasing PaO2/FiO2, improving lung compliance, and among the five ventilation strategies for postoperative atelectasis, VCV+highPEEP+RM had the greatest potential to reduce atelectasis caused by inflammation.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021288941.

Abstract The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

Abstract Background Heterogeneity of metastatic renal cell carcinoma (RCC) constraints accurate prognosis prediction of the tumor. We therefore aimed at developing a novel nomogram for accurate prediction of overall survival (OS) of patients with metastatic RCC. Methods We extracted 2010 to 2016 data for metastatic RCC patients in the Surveillance, Epidemiology, and End Results (SEER) database, and randomly stratified them equally into training and validation sets. Prognostic factors for OS were analyzed using Cox regression models, and thereafter integrated into a 1, 3 and 5-year OS predictive nomogram. The nomogram was validated using the training and validation sets. The performance of this model was evaluated by the Harrell’s concordance index (C-index), calibration curve, integrated discrimination improvement (IDI), category-free net reclassification improvement (NRI), index of prediction accuracy (IPA), and decision curve analysis (DCA). Results Overall, 2315 metastatic RCC patients in the SEER database who fulfilled our inclusion criteria were utilized in constructing a nomogram for predicting OS of newly diagnosed metastatic RCC patients. The nomogram incorporated eight clinical factors: Fuhrman grade, lymph node status, sarcomatoid feature, cancer-directed surgery and bone, brain, liver, and lung metastases, all significantly associated with OS. The model was superior to the American Joint Committee on Cancer (AJCC) staging system (7th edition) both in training (C-indices, 0.701 vs. 0.612, P

The rapid spread of COVID-19 in Ethiopia was attributed to joint effects of multiple factors such as low adherence to face mask-wearing, failure to comply with social distancing measures, many people attending religious worship activities and holiday events, extensive protests, country election rallies during the pandemic, and the war between the federal government and Tigray Region. This study built a system dynamics model to capture COVID-19 characteristics, major social events, stringencies of containment measures, and vaccination dynamics. This system dynamics model served as a framework for understanding the issues and gaps in the containment measures against COVID-19 in the past period (16 scenarios) and the spread dynamics of the infectious disease over the next year under a combination of different interventions (264 scenarios). In the counterfactual analysis, we found that keeping high mask-wearing adherence since the outbreak of COVID-19 in Ethiopia could have significantly reduced the infection under the condition of low vaccination level or unavailability of the vaccine supply. Reducing or canceling major social events could achieve a better outcome than imposing constraints on people's routine life activities. The trend analysis found that increasing mask-wearing adherence and enforcing more stringent social distancing were two major measures that can significantly reduce possible infections. Higher mask-wearing adherence had more significant impacts than enforcing social distancing measures in our settings. As the vaccination rate increases, reduced efficacy could cause more infections than shortened immunological periods. Offsetting effects of multiple interventions (strengthening one or more interventions while loosening others) could be applied when the levels or stringencies of one or more interventions need to be adjusted for catering to particular needs (e.g., less stringent social distancing measures to reboot the economy or cushion insufficient resources in some areas).

Abstract Purpose This study aimed to establish a nomogram to predict the long‐term overall survival (OS) for patients with penile squamous cell carcinoma (PSCC). Method The PSCC patients receiving regional lymph node dissection (RLND) were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The dataset of all eligible patients were used to develop the predictive model. The significant independent predictors were identified through Cox regression modeling based on the Bayesian information criterion and then incorporated into a nomogram to predicted 1‐, 3‐, and 5‐year OS. Internal validation was performed using the bootstrap resampling method. The model performance was evaluated using Harrell's concordance index (C‐index), calibration plots, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA). Results Totally, 384 eligible PSCC patients were enrolled from the SEER database. A nomogram for OS prediction was developed, in which three clinical variables significantly associated with OS were integrated, including age, N classification, and log odds of positive lymph nodes (LODDS). The C‐index of the nomogram (0.746, 95% CI: 0.702‐0.790) was significantly higher than that of the American Joint Committee on Cancer (AJCC) staging system (0.692, 95% CI: 0.646‐0.738, P = .020). The bootstrap optimism‐corrected C‐index for the nomogram was 0.739 (95% CI: 0.690‐0.784). The bias‐corrected calibration plots showed the predicted risks were in good accordance with the actual risks. The results of NRI, IDI, and DCA exhibited superior predictive capability and higher clinical use of the nomogram compared with the AJCC staging system. Conclusion We successfully constructed a simple and reliable nomogram for OS prediction among PSCC patients receiving RLND, which would be beneficial to clinical trial design, patient counseling, and therapeutic modality selection.

We have investigated the thermoelectric properties of a pristine MoO3 monolayer and its defective structures with different oxygen vacancies using first-principles methods combined with Boltzmann transport theory. Our results show that the thermoelectric properties of the MoO3 monolayer exhibit an evident anisotropic behavior which is caused by the similar anisotropy of the electrical and thermal conductivity. The thermoelectric materials figure of merit (ZT) value along the x- and the y-axis is 0.72 and 0.08 at 300 K, respectively. Moreover, the creation of oxygen vacancies leads to a sharp peak near the Fermi level in the density of states. This proves to be an effective way to enhance the ZT values of the MoO3 monolayer. The increased ZT values can reach 0.84 (x-axis) and 0.12 (y-axis) at 300 K.

Abstract Background The suicide risk was higher in kidney cancer patients than in the general population. The purpose of this study was to characterize the suicide rates among kidney cancer patients and to identify the potential risk factors associated with suicide from the Surveillance, Epidemiology, and End Results (SEER) database. Methods Kidney cancer patients were identified from the SEER database during 1973‐2015. Suicide rates and standardized mortality ratios (SMRs) of this population were calculated, and the US general population during 1981‐2015 was chosen as a reference. Univariable and multivariable Cox regression were performed to find out potential risk factors of suicide. Results There were 207 suicides identified among 171 819 individuals with kidney cancer observed for 948 272 person‐years. The suicide rate was 21.83 per 100 000 person‐years, and SMR was 1.83 (95% CI: 1.59‐2.10). On Cox regression, diagnosis in early years (1973‐1982 vs 2003‐2015, HR: 2.03, 95% CI: 1.01‐4.11, P = 0.048; 1983‐1992 vs 2003‐2015, HR: 1.99, 95% CI: 1.18‐3.35, P = 0.010), male sex (vs female sex, HR: 4.43, 95% CI: 2.95‐6.65, P

Background: Current diagnostic methods for colorectal cancer (CRC) are colonoscopy and sigmoidoscopy, which are invasive and complex procedures with possible complications. This study aimed to determine models for CRC identification that involve minimally invasive, affordable, portable, and accurate screening variables. Methods: This was a retrospective study that used data from electronic medical records of patients with CRC and healthy individuals between July 2017 and June 2018. Laboratory data, including liver enzymes, lipid profiles, complete blood counts, and tumor biomarkers, were extracted from the electronic medical records. Five machine learning models (logistic regression, random forest, k-nearest neighbors, support vector machine [SVM], and naïve Bayes) were used to identify CRC. The performances were evaluated using the areas under the curve (AUCs), sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV). Results: A total of 1164 electronic medical records (CRC patients: 582; healthy controls: 582) were included. The logistic regression model achieved the highest performance in identifying CRC (AUC: 0.865, sensitivity: 89.5%, specificity: 83.5%, PPV: 84.4%, NPV: 88.9%). The first four weighted features in the model were carcinoembryonic antigen (CEA), hemoglobin (HGB), lipoprotein (a) (Lp(a)), and high-density lipoprotein (HDL). A diagnostic model for CRC was established based on the four indicators, with an AUC of 0.849 (0.840-0.860) for identifying all CRC patients, and it performed best in discriminating patients with late colon cancer from healthy individuals with an AUC of 0.905 (0.889-0.929). Conclusions: The logistic regression model based on CEA, HGB, Lp(a), and HDL might be a powerful, noninvasive, and cost-effective method to identify CRC.

Hijacking host ubiquitin pathways is essential for the replication of diverse viruses. However, the role of deubiquitinating enzymes (DUBs) in the interplay between viruses and the host is poorly characterized. Here, we demonstrate that specific DUBs are potent inhibitors of viral proteins from HIVs/simian immunodeficiency viruses (SIVs) that are involved in viral evasion of host restriction factors and viral replication. In particular, we discovered that T cell-functioning ubiquitin-specific protease 8 (USP8) is a potent and specific inhibitor of HIV-1 virion infectivity factor (Vif)-mediated apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3)G (A3G) degradation. Ectopic expression of USP8 inhibited Vif-induced A3G degradation and suppressed wild-type HIV-1 infectivity even in the presence of Vif. In addition, specific DUBs repressed Vpr-, Vpu-, and Vpx-triggered host restriction factor degradation. Our study has revealed a previously unrecognized interplay between the host’s DUBs and viral replication. Enhancing the antiviral activity of DUBs therefore represents an attractive strategy against HIVs/SIVs.

Surfactants and cosolvents are often combined to solubilize insoluble drugs in commercially available intravenous formulations to achieve better solubilization. In this study, six marketed parenteral formulations with surfactants and cosolvents were investigated on the aggregation processes of micelles, the structural characterization of micelles, and the properties of solvent using molecular dynamics simulations. The addition of cosolvents resulted in better hydration of the core and palisade regions of micelles and an increase in both radius of gyration (Rg) and the solvent accessible surface area (SASA), causing a rise in critical micelle concentration (CMC), which hindered the phase separation of micelles. At the same time, the presence of cosolvents disrupted the hydrogen bonding structure of water in solution, increasing the solubility of insoluble medicines. Therefore, the solubilization mechanism of the cosolvent and surfactant mixtures was successfully analyzed by molecular dynamics simulation, which will benefit future formulation development for drug delivery.

Vaccines are one of the most successful medical inventions to enable the eradication or control of common and fatal diseases. Environmental exposure of hosts, including helminth infections, plays an important role in immune responses to vaccines. Given that helminth infections are among the most common infectious diseases in the world, evaluating vaccine efficiency in helminth-infected populations may provide critical information for selecting optimal vaccination programs. Here, we reviewed the effects of helminth infections on vaccination and its underlying immunological mechanisms, based on findings from human studies and animal models. Moreover, the potential influence of helminth infections on SARS-CoV-2 vaccine was also discussed. Based on these findings, there is an urgent need for anthelmintic treatments to eliminate helminth suppressive impacts on vaccination effectiveness during implementing mass vaccination in parasite endemic areas.

Alterations in the composition and configuration of land uses during urbanization exert significant impacts on variations in soil phosphorus (P). Here, we analyzed the concentrations of soil total P and P fractions in 75 soil samples from vegetated lands with different urbanization intensity (UI) in western Chengdu, China. Characteristics of land use spatial pattern were investigated in 300 m buffer zones around each soil sample location according to five landscape metrics. The relationships between soil P variations and land use spatial patterns were analyzed by stepwise multiple regression. The results show that land uses exhibited highly fragmented, complex and heterogeneous features with increasing UI; concentrations of soil total P and P fractions, except for residual P, displayed accumulated trends. The built-up land and traffic green land predominated in medium- and high-UI landscapes and showed positive relationships with the soil P. By contrast, the cultivated land, forest land and industrial green land were more commonly distributed in low-UI landscapes and showed negative correlations with soil P. Furthermore, park green land, residential green land and public green land occupied small proportions of the study area and exhibited varied associations with soil P in landscapes with varied UI. The main factors affecting the soil P variations were the proportion of forest land, patch shape and landscape dispersion in a low-UI landscape. Soil P variations in medium-UI landscapes were controlled by the proportions of built-up land and residential green land, landscape dispersion and diversity. Additionally, soil P variations in high-UI landscapes only were regulated by the proportions of built-up land and public green land. The results reveal that the development of a variety of landscape planning schemes for different UI landscapes can be pivotal to maintaining or improving soil P balance, obtaining functional soil ecosystems, and securing a low environmental risk in urbanized areas.

The development of a safe and efficient multivalent vaccine has great prospects for application. Both rabies virus (RABV) and canine distemper virus (CDV) are highly infectious antigens, causing lethal diseases in domestic dogs and other carnivores worldwide. In this study, a replication-deficient human adenovirus 5 (Ad5)-vectored vaccine, rAd5-G-H, expressing RABV glycoprotein (G) and CDV hemagglutinin (H) protein was constructed. The RABV G and CDV H protein of rAd5-G-H were expressed and confirmed in infected HEK-293 cells by indirect immunofluorescence assay. The rAd5-G-H retained a homogeneous icosahedral morphology similar to rAd5-GFP under an electron microscope. A single dose of 108 GFU of rAd5-G-H administered to mice by intramuscular injection elicited rapid and robust neutralizing antibodies against RABV and CDV. Flow cytometry assays indicated that the dendritic cells and B cells in inguinal lymph nodes were significantly recruited in rAd5-G-H-immunized mice in comparison with the mock and rAd5-GFP groups. rAd5-G-H also activated the Th1- and Th2-mediated cell immune responses against RABV and CDV in mice, which contributed to 100% survival of a lethal-dose RABV challenge without any clinical signs. In foxes, a single dose of 109 GFU of rAd5-G-H could elicit high levels of neutralizing antibodies against both RABV and CDV in comparison with the mock and rAd5-GFP groups. All foxes in the rAd5-GFP and mock groups died, while the foxes inoculated with rAd5-G-H all survived and showed no clinical signs of disease after being challenged with a lethal wild-type CDV strain. These results suggested that rAd5-G-H has great potential as a bivalent vaccine against rabies and canine distemper in highly susceptible dogs and wildlife animals.

Both severe fever with thrombocytopenia syndrome (SFTS) and rabies are severe zoonotic diseases. As co-hosts of rabies virus (RABV) and SFTS virus (SFTSV), dogs and cats could not only be infected but also transmit the virus to human. Hence, developing a bivalent vaccine against both SFTS and rabies is urgently needed. In this study, we generated a recombinant replication-deficient human adenovirus type 5 (Ad5) co-expressing RABV G and SFTSV Gn (Ad5-G-Gn) and evaluated its immunogenicity and efficacy in mice. Ad5-G-Gn immunization activated more dendritic cells (DCs) and B cells in lymph nodes (LNs) and induced Th1-/Th2-mediated responses in splenocytes, leading to robust production of neutralizing antibodies against SFTSV and RABV. In addition, single dose of Ad5-G-Gn conferred mice complete protection against lethal RABV challenge and significantly reduced splenic SFTS viral load. Therefore, our data support further development of Ad5-G-Gn as a potential bivalent vaccine candidate against SFTS and rabies for dog and cat use.

Background: Propofol is a widely used anesthetic. Whether propofol inhibits androgen production by rat Leydig cells and the underlying mechanism remains unclear. The objective of the current study was to examine the effects of propofol exposure to rat primary immature Leydig cells and to define propofol-induced inhibition of steroidogenic enzymes in both rat and human testes in vitro.Methods: Immature Leydig cells were purified from 35-day-old male Sprague–Dawley rats and were exposed to propofol for 3 h. The androgen production by Leydig cells under basal, luteinizing hormone, 8bromo-cAMP, and steroid-substrate stimulated conditions and gene expression of Leydig cells after exposure to propofol were measured. Immature Leydig cells were treated with propofol for 3 h and switched to propofol-free medium for additional 3 and 9 h to test whether propofol-induced inhibition is reversible. 3H-Steroids were used to evaluate the direct action of propofol on cytochrome P450 cholesterol side chain cleavage (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1), and 17β-hydroxysteroid dehydrogenase 3 (HSD17B3) activities in rat and human testes in vitro.Results: Propofol significantly lowered luteinizing hormone and 8bromo-cAMP stimulated androgen production by Leydig cells after 3-h exposure. Further investigation showed that propofol down-regulated the expression of Cyp11a1 and Cyp17a1 and their proteins at 5 and 50 µM, although it up-regulated Lhcgr expression at 50 µM. Propofol significantly suppressed phosphorylation of ERK1/2 and induced ROS production in immature Leydig cells at 5 and 50 µM. Propofol significantly induced apoptosis of immature Leydig cells at 50 µM. Propofol specifically inhibited rat and human testis HSD3B activities in vitro. The half maximal inhibitory concentrations of propofol for rat and human HSD3B enzymes were 1.011 ± 0.065 and 3.498 ± 0.067 µM, respectively. The mode of action of propofol of inhibiting HSD3B was competitive when pregnenolone was added. At 50 µM, propofol did not directly inhibit rat and human testis CYP11A1, CYP17A1, and HSD17B3 activities in vitro.Conclusion: Propofol inhibits androgen production via both directly inhibiting HSD3B activity and down-regulating Cyp11a1 and Cyp17a1 expression in Leydig cells. Suppression of steroidogenic enzymes is presumably associated with the lower production of androgen by Leydig cells after propofol treatment. However, propofol-induced inhibition on androgen production is reversible.

A more babyfaced individual is perceived as more child-like and this impression from babyface, as known as babyface effect, has an impact on social life among various age groups. In this study, the influence of babyfaces on visual selective attention was tested by cognitive task, demonstrating that the female babyface and male mature face would draw participants’ attention so that they take their eyes off more slowly. In Experiment 1, a detection task was applied to test the influence of babyfaces on visual selective attention. In this experiment, a babyface and a mature face with the same gender were presented simultaneously with a letter on one of them. The reaction time was shorter when the target letter was overlaid with a female babyface or male mature face, suggesting an attention capture effect. To explore how this competition influenced by attentional resources, we conducted Experiment 2 with a spatial cueing paradigm and controlled the attentional resources by cueing validity and inter-stimulus interval. In this task, the female babyface and male mature face prolonged responses to the spatially separated targets under the condition of an invalid and long interval pre-cue. This observation replicated the result of Experiment 1. This indicates that the female babyface and male mature face glued visual selective attention once attentional resources were directed to them. To further investigate the subliminal influence from a babyface, we used continuous flash suppression paradigm in Experiment 3. The results, again, showed the advantage of the female babyfaces and male mature faces: they broke the suppression faster than other faces. Our results provide primary evidence that the female babyfaces and male mature faces can reliably glue the visual selective attention, both supra- and sub-liminally.

Previous research stresses that system justifying belief can weaken corruption perception, by this possibly fostering unjust behaviors. However, general results of the effect of general system justification on corruption are ambiguous, indicating also a lessening impact. We conducted a line of studies trying to elucidate these circumstances by testing the effect of general system justification on corruption perception and intention. In addition, we explored institutional trust as a possible mediator in this process. For this purpose we conducted three studies. The first two studies examined the association between general system justification and corruption. In Study 1, a correlational design was run using questionnaires to assess the relation between general system justification and corruption perception as well as corruption intention. In Study 2, an experimental design was conducted manipulating general system justification via exposure to high or low system threat condition, then measuring its effect on corruption perception and corrupt intention. In Study 3, two sub-studies using correlational and experimental designs were run to explore the mediating role of institutional trust, respectively. Results replicated former studies showing that general system justification is negatively associated with corruption perception. However, they also showed a negative correlation with corrupt intention. Furthermore, they showed that institutional trust mediated the relation between general system justification and corruption. We suggest to consider these findings to further elucidate the psychological basis underlying different effects of general system justification on human behaviors.

The present set of studies aimed to explore the effect of self-esteem on corrupt intention and the mediating role of materialism in generating this effect. In Study 1, we used questionnaires to investigate the correlation among self-esteem, materialism and corrupt intention. In Study 2, we manipulated self-esteem to explore the causal effect of self-esteem on materialism and corrupt intention. In Study 3, we manipulated materialism to examine whether inducing materialism can reduce the relationship between self-esteem and corrupt intention. The three studies converged to show that increased self-esteem caused a low level of materialism, which in turn decreased corrupt intention. The theoretical and practical implications of the results are discussed.

Enterovirus 68 (EVD68) causes respiratory illness, mostly in children. Despite a reported low-level of transmission, the occurrence of several recent outbreaks worldwide including the 2014 outbreak in North America has raised concerns regarding the pathogenesis and evolution of EVD68. To elucidate the phylogenetic features of EVD68 and possible causes for the 2014 outbreak, 216 EVD68 strain sequences were retrieved from Genbank, including 22 from the 2014 outbreak. Several geographic and genotypic origins were established for these 22 strains, 19 of which were classified as Clade B. Of these 19 strains, 17 exhibited subsequent clustering and variation in protein residues involved in host-receptor interaction and/or viral antigenicity. Approximately 18 inter-clade variations were detected in VP1, which led to the identification of a new Clade D in EVD68 strains. The classification of this new clade was also verified by the re-construction of a Neighbor-Joining tree during the phylogenetic analysis. In addition, our results indicate that members of Clade B containing highly specific alterations in VP1 protein residues were the foremost contributors to the 2014 outbreak in the US. Altered host-receptor interaction and/or host immune recognition may explain the evolution of EVD68 as well as the global emergence and ongoing adaptation of this virus.

To provide a basis for using indigenous bacteria for bioremediation of heavy metal contaminated soil, the heavy metal resistance and plant growth-promoting activity of 136 isolates from V-Ti magnetite mine tailing soil were systematically analyzed. Among the 13 identified bacterial genera, the most abundant genus was Bacillus (79 isolates) out of which 32 represented B. subtilis and 14 B. pumilus, followed by Rhizobium sp. (29 isolates) and Ochrobactrum intermedium (13 isolates). Altogether 93 isolates tolerated the highest concentration (1000 mg kg(-1)) of at least one of the six tested heavy metals. Five strains were tolerant against all the tested heavy metals, 71 strains tolerated 1,000 mg kg(-1) cadmium whereas only one strain tolerated 1,000 mg kg(-1) cobalt. Altogether 67% of the bacteria produced indoleacetic acid (IAA), a plant growth-promoting phytohormone. The concentration of IAA produced by 53 isolates was higher than 20 µg ml(-1). In total 21% of the bacteria produced siderophore (5.50-167.67 µg ml(-1)) with two Bacillus sp. producing more than 100 µg ml(-1). Eighteen isolates produced both IAA and siderophore. The results suggested that the indigenous bacteria in the soil have beneficial characteristics for remediating the contaminated mine tailing soil.