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BackgroundUterine leiomyosarcoma (uLMS) accounts for roughly 70% of all uterine sarcomas, with recurrence and mortality rates notably higher than those of other uterine tumors. The prognosis of uLMS patients who have distant metastases remains poor. The objective of this study was to determine independent risk variables related to distant metastases in patients with uLMS and prognostic factors for those with distant metastases. Subsequently, two practical nomograms were developed and validated to assess the probability of distant metastases and predict survival outcomes for these with distant metastases, respectively.MethodsA real-world retrospective study was carried out using data from patients diagnosed with primary uLMS in the Surveillance, Epidemiology, and End Results (SEER) database spanning the years 2010 to 2015. Univariate and multivariate logistic regression analyses were utilized to identify clinicopathological characteristics related to the risk of distant metastases, while univariate and multivariate Cox regressions were employed to determine prognostic factors. Then, a risk nomogram incorporating independent risk variables and a prognostic nomogram integrating independent prognostic factors were established in the training cohort and validated for accuracy in the validation cohort, respectively. Receiver operating characteristic (ROC) curves, area under the curve (AUC), and calibration curves were utilized to measure the accuracy of nomograms, while decision curve analysis (DCA) curves were employed to assess their clinical benefit capacity. Based on the median total point derived from the prognostic nomogram, patients were stratified into high- and low-risk groups. The differentiation ability of the prognostic nomogram was evaluated using Kaplan-Meier survival analysis with the log-rank test.ResultsThe study encompassed 1,362 patients diagnosed with uLMS, among whom 337 cases (24.7%) manifested synchronous distant metastases at the initial diagnosis. Univariate and multivariate logistic regression analyses identified race, histological grade, T stage, N stage, tumor size, surgery, and chemotherapy as independent risk factors for distant metastases in uLMS patients. The outcomes of both univariate and multivariate Cox analyses indicated that surgery and chemotherapy emerged as independent protective factors for prognosis in uLMS patients with distant metastases, whereas higher histological grade and T stage were identified as independent risk factors. The risk nomogram incorporating independent risk variables and the prognostic nomogram integrating independent prognostic factors could respectively predict the risk of metastases and the prognosis very effectively in both training and validation cohorts.ConclusionsIn summary, we developed the novel well-validated risk nomogram to precisely assess the probability of metastases in uLMS patients and prognostic nomogram to predict the prognosis of those with distant metastases, providing decision-making guidance for tailoring individualized clinical management of these patients.

Abstract Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody.

ABSTRACT: Chicken egg chalaza (CLZ) is a natural colloidal structure in eggs that exists as an egg yolk stabilizer and is similar in composition to egg white. In this study, the proteome, phosphoproteome, and N-glycoproteome of CLZ were characterized in depth. We hydrolyzed the CLZ proteins and enriched the phosphopeptides and glycopeptides. We identified 45 phosphoproteins and 80 N-glycoproteins, containing 59 phosphosites and 203 N-glycosylation sites, respectively. Typically, the ovalbumin in CLZ was both phosphorylated and N-glycosylated, with 4 phosphosites and 4 N-glycosylation sites. Moreover, we identified 2 N-glycosylated subunits of ovomucin, mucin-5B and mucin-6, with 32 and nine N- glycosylation sites, respectively. Analysis of the phosphorylation and N-glycosylation status of CLZ proteins could provide novel insights into the structural and functional characteristics of CLZ.

Membrane characteristics are determined by the fatty acids composition, which affects survival rates after freeze-drying. However, it is unknown which composition provides the greatest effect. In this study, we found that the addition of Tween 80 and Tween 20 significantly increased survival rates of Lactiplantibacillus plantarum, which reached a maximum of 93.1 %. Conversely, Tween 60 caused a significant decrease. We further found that the difference between the effects of adding Tween 80 and Tween 60 was the change in oleic acid contents. To verify the role of oleic acid, we used CRISPR-Cas9 to knock-out the key synthesis gene cla-er. The survival rates of L. plantarum AR113Δcla-er declined to 5.48 %. The addition of oleic acid restored the rates to those of wild type strains. Moreover, the membrane integrity and fluidity of knockout strains markedly decreased. This is the first confirmation that Tween 80 or Tween 20 increases the survival rate by increasing the content of oleic acid in the cell membrane. These findings also indicated that oleic acid in cell membranes has a substantial protective effect on L. plantarum during freeze-drying.

BackgroundFunctional dyspepsia (FD) refers to a group of clinical symptoms caused by gastric and duodenal dysfunction. Which is a chronic functional disorder of the gastrointestinal tract with no cure. Zhishixiaopi decoction (ZSXP) is a type of Chinese herbal prescription that for treating FD. Although some randomized controlled trials (RCTs) report that ZSXP can significantly improve FD clinical symptoms and/or laboratory results, the trial design varies greatly among studies, making it challenging to draw a conclusion of the efficacy of ZSXP in treating FD.DesignA systematic review and a meta-analysis.SettingMianyang Central Hospital.ObjectiveWe conducted a systematic review and a meta-analysis to evaluate the efficacy and safety of ZSXP for treating FD.MethodsWe developed inclusion and exclusion criteria based on FD diagnosed criteria, interventions to treat FD, and outcomes of these interventions. Search strategies combined disease terms, symptom terms, anatomy terms and intervention terms. Literature search was conducted on eight online databases in English or Chinese, including Medline (via PubMed), Embase (via Ovid), The Cochrane Library, Web of Science, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang Database.InterventionThe experimental group received oral administration of ZSXP and had a complete treatment process. ZSXP needs to fully contain the key herbal ingredients, regardless of whether the dosage of each herb is consistent with the original prescription. The Control group received monotherapy or combination therapy of other Western medicine and had a complete treatment process.OutcomesThe primary outcomes appraised were Total effective rate (TER), serum levels of Motilin(MOT), Gastrin(GAS) and Somatostatin (SS), Gastric emptying rate (GER) using a Barium meal method (GER(B)) and Gastric half emptying time using an Ultrasonic method (GHET(T1/2)). The Cochrane Bias Risk Tool was used for quality critical appraisal, Review Manager (RevMan) version 5.3 was used for statistical analysis.ResultsA total of 21 medium-quality RCTs were included in the meta-analysis. All 21 included studies were conducted and completed in Mainland China from 1998 to 2020. The treatment duration was between two weeks to two months. The meta-analysis suggests that, compared with the Western medicine treatment group, ZSXP treatment was more effective to improving the TER in FD [Odds ratio, OR = 3.54, 95%CI:(2.49, 5.05), Z = 6.99, PConclusionsThe meta-analysis suggests that Zhishixiaopi treatment is a relatively effective and safe traditional Chinese medicine prescription and could be used for functional dyspepsia treatment. Considering the limitations of this study, the conclusion needs to be further confirmed by high-quality, multi-center, and large-sample randomized controlled trials.

The installation of successional heating devices in industrial buildings will result in thermal corridors. To improve the thermal environment in and around these corridors, buoyancy-driven ventilation is commonly utilized to dissipate heat, which is based on the natural convection design for buildings. However, the flow and heat exchange patterns of natural convection related to thermal corridors have not been clearly clarified, and no relevant correlations have been established to quantify them. The conducted numerical study aimed to analyze the flow and heat transfer characteristics of natural convection within thermal corridors in industrial buildings. Experimental data were utilized to validate a computational fluid dynamics (CFD) model developed for this purpose. The study considered the influence of various parameters on the results obtained. In the side corridor, the prevalence of reverse flow dominates much of the channel, while in the middle corridor, reverse flow near the bottom corner is observed. The ambient air temperature significantly impacts the temperature distribution in both corridors. Increasing the ambient air temperature at the inlet from 22 to 28 °C results in a substantial temperature rise within the corridor, by approximately 6–7 °C. When the outlet size is constant and the inlet size drops by 30%, the air temperature in the corridor increases by 3 °C. Finally, correlations were established based on the simulation data to predict the surface-averaged Nu¯ of the heated wall and the induced mass flow rate, m˙, of the natural convection. The correlations have relative errors of less than 16% when compared to the simulation data.

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.

Pomegranate (Punica granatum L.), with its abundant phenolic substances and strong antioxidant activity, holds significant research and utilization potential across various organs. However, there have been few studies on the phenolic content and antioxidant activity of different parts of pomegranate, especially the placenta. This study investigated the phenolic content and antioxidant activity of fruits, flowers, and leaves of two pomegranate varieties, ‘Tunisia’ and ‘Qingpi’, throughout their growth and development. Results indicated significant variations in phenolic content among different organs, with petals exhibiting the highest total polyphenol content (TPC, 49.40 mg GAE/g FW) and total anthocyanin content (TMAC, 1938.54 nmol/g FW). Placenta contained the highest levels of total flavonoids (TFC, 173.58 mg RE/g FW) and punicalagin (109.30 mg/g FW). The peel had the highest content of total flavanols (TFAC, 19.42 mg CE/g FW). Over the course of pomegranate development, total polyphenols, total flavonoids, total flavanols, punicalagin, and antioxidant activity declined in different organs. Antioxidant activity followed the order: fruit > flower > leaf, with the placenta exhibiting the highest antioxidant activity among fruits. Antioxidant activity showed a significant positive correlation with total polyphenols (R2 = 0.77-1.00), total flavonoids (R2 = 0.71-0.99, except tegmens), and punicalagin (R2 = 0.71-1.00). This study provides a comparative analysis of the phenolic content and antioxidant activity in different organs of pomegranate, highlighting the placenta as the primary source of punicalagin. This study provides a theoretical basis for the development and utilization of pomegranate phenolic compounds.

Currently, the use of robots has altered the way people live and their lifestyles. To realize a human-computer interaction system based on robots’ comprehension of human emotions, this study chooses facial expressions as the research object and constructs a facial expression recognition model based on convolutional neural networks and channel attention. To deploy the recognition model to portable devices, a depth-separable convolution filter pruning algorithm based on principal component analysis is constructed. This model applies principal component analysis to reduce the dimensionality of similar filter matrices obtained by calculating geometric medians to prevent gradient explosion. The proposed algorithm for facial expression recognition in this study achieves a 99% recognition accuracy with an average of 80.39%, while using the least number of parameters among the compared algorithms. The verification experiment results of lightweight network show that when the model depth is 56 and the pruning rate is 40%, the correct rate of facial expression recognition of the network model based on the pruning strategy proposed in the study is 93.24%. When dimension is 0.85, the accuracy of model classification is the highest. The algorithm presented in this study exhibits excellent performance when recognizing facial expressions, demonstrating notable robustness and efficiency. The pruning strategy proposed in this study has a good model acceleration effect. It can not only reduce the memory occupied by about 41% of parameters, but also improve the classification accuracy, running time and calculation cost after pruning to a certain extent. The study applied deep separable convolution and PCA techniques to improve and reduce the dimensionality of the convolutional layer in the ResNet network structure, and improved the comparable filter matrix generated during the filter pruning process.

With the rapid development of computer vision and artificial intelligence, image conversion technology has been widely applied in the fields of digital media and art. Based on the Generative adversarial network, this paper proposes a painting image conversion algorithm for multi class scenes. It performs deep feature extraction in the residual module, divides the encoding and decoding parts of the generator into functional parts, and designs them separately. The mixed attention module is inserted into the decoder and encoder to preserve the texture details of the image. The deep network interpolation is incorporated to achieve smooth and continuous conversion of the painting image. The experiment showed that the loss value of the research method decreases to 0.008 after 400 iterations during the loss value testing. Its maximum peak signal-to-noise ratio is 34.9dB when the bit rate increases to 1000kb/s. In the SAR image conversion dataset, the F1 value increases to 97.4 after 200 iterations. The pixel loss when it reaches 100% conversion in outdoor images is 5.38k. The data indicates that the research method has good performance in painting image conversion and can provide effective technical references for image conversion.

Background: An inactivated poliomyelitis vaccine made from Sabin strains (sIPVs) has widely been used in China since 2015. However, the quantitative data on the instant and persistent inhibition effects of maternal poliovirus antibodies on the immune response to sIPV priming and booster vaccination have not been available yet. Objective: In this study, we aim to explore and quantify the instant and persistent inhibition effect of maternal poliovirus antibodies on the immune response elicited by sIPV primary and booster vaccination. Methods: The immunogenicity data consisting of the days 0 and 30 after the prime and booster vaccination of the sIPV in a phase IV trial were pooled for a quantitative analysis of the inhibition effect of maternal poliovirus antibody. The geometric mean ratio (GMR) was calculated using linear regression models, representing that every 2-fold higher maternal poliovirus antibody titer may result in a (1-GMR) lower postimmunization antibody titer. Results: The GMRs for poliovirus types 1, 2, and 3 were 0.79 (0.77–0.82), 0.85 (0.81–0.89), and 0.87 (0.83–0.91) at 30 days after the priming series, 0.86 (0.83–0.89), 0.81 (0.76–0.85), and 0.86 (0.80–0.93) at one year after the priming series, and 0.96 (0.94–0.99), 0.89 (0.86–0.93), and 0.98 (0.93–1.03) at 30 days after the booster dose. The inhibition effect continued to exist until the booster dose 1 year later, and such a persistent inhibition effect was almost attenuated for poliovirus types 1 and 3, and partly reduced for type 2 at 30 days after the booster dose. Conclusion: A wider interval between the four sIPV doses might be a consideration for reducing the effect of maternal antibodies and subsequently eliciting and maintaining higher antibody levels to protect against poliovirus transmission and infection at the final stage of polio eradication in the global world. This study’s clinical trial registry number is NCT04224519.

The development of broad-spectrum antivirals against human coronaviruses (HCoVs) is critical to combat the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, as well as future outbreaks of emerging CoVs. We have previously identified a polyethylene glycol-conjugated (PEGylated) lipopeptide, EK1C4, with potent pan-CoV fusion inhibitory activity. However, PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo. Therefore, we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment (HR2-CF) of HCoV-OC43. Among these lipopeptides, EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike (S) mutants, as well as other HCoVs and some bat SARS-related coronaviruses (SARSr-CoVs) tested. The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes, better metabolic stability in mouse serum, higher thermostability than the PEGylated lipopeptide EK1C4, suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.

Summary: The transfer of endocytosed cargoes to lysosomes (LYSs) requires HOPS, a multiprotein complex that tethers late endosomes (LEs) to LYSs before fusion. Many proteins interact with HOPS on LEs/LYSs. However, it is not clear whether these HOPS interactors localize to LEs or LYSs or how they participate in tethering. Here, we biochemically characterized endosomes purified from untreated or experimentally manipulated cells to put HOPS and interacting proteins in order and to establish their functional interdependence. Our results assign Rab2a and Rab7 to LEs and Arl8 and BORC to LYSs and show that HOPS drives LE-LYS fusion by bridging late endosomal Rab2a with lysosomal BORC-anchored Arl8. We further show that Rab7 is absent from sites of HOPS-dependent tethering but promotes fusion by moving LEs toward LYSs via dynein. Thus, our study identifies the topology of the machinery for LE-LYS tethering and elucidates the role of different small GTPases in the process.

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.

Sichuan is the China’s leading producer of loquat, with the largest cultivation area and yield ranked first in China. Loquat is a seasonal fruit highly appreciated by consumers; however, the fruit is prone to browning and lignification after harvest, affecting its storage quality. The effects of L-Cysteine (L-Cys, 0.01, 0.05, 0.1, 0.2%) and γ-aminobutyric acid (GABA, 0.025, 0.05, 0.075, 0.1%) on the sensory quality and antioxidant activity of loquat fruit during cold storage at 4 °C for 35 days and simulated shelf life for 5 days were investigated. The results showed that after 40 days of storage, compared with the control, 0.05% L-Cys and 0.05% GABA treatment of ‘Zaozhong No. 6’ loquat fruit effectively reduced the weight loss rate, browning index, decay index, respiratory rate, firmness, and lignin content and slowed the decreases in total soluble solids, soluble sugar, titratable acidityand vitamin C contents. The application of 0.05% L-Cys and 0.05% GABA significantly increased the contents of total phenols, total flavonoids, flavanols, and carotenoids; delayed the increase of relative electric conductivity, MDA, POD, and PPO activities; and significantly enhanced the activities of SOD and CAT, DPPH free radical scavenging ability, and FRAP, thereby improving antioxidant capacity. In summary, 0.05% L-Cys and 0.05% GABA treatment promotes the quality of loquat fruit after 40 days of storage, and significantly enhances antioxidant capacity, thus delaying senescence after harvest.

We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity. However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral activity. Therefore, we designed and synthesized a dePEGylated lipopeptide, EKL1C, by replacing the PEG linker in EK1C4 with a short peptide. Similar to EK1C4, EKL1C displayed potent inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses. In this study, we found that EKL1C also exhibited broad-spectrum fusion inhibitory activity against human immunodeficiency virus type 1 (HIV-1) infection by interacting with the N-terminal heptad repeat 1 (HR1) of viral gp41 to block six-helix bundle (6-HB) formation. These results suggest that HR1 is a common target for the development of broad-spectrum viral fusion inhibitors and EKL1C has potential clinical application as a candidate therapeutic or preventive agent against infection by coronavirus, HIV-1, and possibly other class I enveloped viruses.

This study measured the lifecycle carbon emissions of buildings in 30 Chinese provinces from 2005 to 2020 and decomposed the drivers of carbon emissions in the materialization stage and operation stage of building, respectively, using the Stochastic Impacts with the Regression on Population, Affluence, and Technology (STIRPAT) model in order to investigate the drivers of carbon emissions and their spatial influence effects in the building sector. The spatial Durbin model (SDM) was used to thoroughly investigate the spatial effects of carbon emissions and their drivers in the building sector under geographic and economic distances. According to the findings, China’s building sector has a high concentration of carbon emissions in the east and a low concentration in the west. There is also a sizable spatial autocorrelation, and the spatial spillover effects in the materialization and operation stages shift in opposite directions. To help the building sector to achieve the carbon peaking and neutrality goals, specific policy recommendations are made based on the study’s findings.

Objective: Intern nurses will play an important role in the use of vaccination to prevent cervical cancer. This study assesses the knowledge about human papillomavirus (HPV) infection and cervical cancer prevention among intern nurses. Methods: We developed a questionnaire to investigate intern nurses' knowledge about HPV infection and cervical cancer prevention. Participants included 323 intern nurses from eight schools. Results: The effective response rate was 79.8%. Some (7.0%) knew that early-stage cervical cancer is commonly asymptomatic. Only 9.7% knew that infection is generally asymptomatic and 20.5% knew that vaccination has no major side effects. There were differences in gender, age, school type, and place of residence for several questions. Conclusions: This study indicates a low level of knowledge about HPV infection and cervical cancer prevention among intern nurses. Our findings highlight the need for more education in this topic to increase the knowledge of intern nurses.

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.

Plums are widely consumed, contain high levels of phenolic compounds, and have strong antioxidant activity. In this study, the main Sichuan cultivars ‘Qiangcuili’ and ‘Cuihongli’ were used to study the changes in the appearance, internal quality, phenolic compounds, and antioxidant activities during fruit development and the expression of phenolic-compound-related structural genes. The results showed that, during development of the two plums, the total soluble solid and soluble sugar contents were highest at the mature stage. The phenolic contents (total phenol content (TPC), total flavonoid content (TFC), and total flavanol content (TFAC)) trended gradually downward as the fruits of the two cultivars matured, while the total anthocyanin content gradually increased in ‘Cuihongli’. The main phenolic components were neochlorogenic acid, chlorogenic acid, ferulic acid, benzoic acid, rutin, and proanthocyanidin B1. The changes in the DPPH and FRAP scavenging activities decreased with fruit ripening. The antioxidant capacity was positively correlated with the TPC, TFC, and TFAC. In the two cultivars, the total phenols, phenolic components, and antioxidant capacity were higher in the peel than in the pulp. CHS, PAL3, and HCT1 may be the regulatory genes related to the accumulation of phenolic substances in the pericarp and pulp of ‘Qiangcuili’ and ‘Cuihongli’. HCT1 may be an important regulator involved in the accumulation of chlorogenic acid in plums. The changes in the quality of the phenols, phenolic components, and antioxidant activity were elucidated during the development of the main plum cultivars in Sichuan, particularly the changes that provided a theoretical basis for the development of bioactive substances in local plum cultivars.

Abstract Background The simple and caged xanthones from Clusiaceae showed significant antineoplastic activity. This study aims to identify structural diverse xanthones and search for novel antitumor natural products from this family plants. Methods The structures of new compounds 1a and 1b were elucidated mainly through comprehensive NMR and MS spectroscopic data, and their absolute configurations were determined by the comparison of the experimental and calculated electronic circular dichroism. Results A pair of new xanthone enantiomers, (+)- and (−)-cracochinxanthone A (1a and 1b), along with thirty known analogues (2–31), were isolated from extracts of the stems and leaves of C. cochinchinense. Preliminary biological assay of some isolates against HL-60, PC-3, and MDA-MB-231 cancer cell lines. Conclusion Some isolated xanthones exhibited high sensitivity against three human malignant cell lines and the structure–activity relationship study showed that the prenyl and geranyl units may play an important role in antitumor activity.

Virus inactivator can inactivate cell-free virions without relying on their replication cycle, potentially reducing the impact of viral infection on cells. Previously, we successfully constructed a HIV-1 protein inactivator, 2DLT, by conjugating the D1D2 region of CD4 to the fusion inhibitor T1144 via a 35-amino acid linker. Therefore, it targets both the CD4 binding site in gp120 and NHR region in gp41. Considering that small-molecule agents have the advantages of fast production, low cost, good stability, and oral availability, we herein report the design of a new small-molecule HIV-1 inactivator, FD028, by conjugating FD016 (an analog of NBD-556, a gp120-CD4 binding inhibitor) with FD017 (an analog of 11d, an HIV-1 fusion inhibitor). The results showed that FD028 inactivated cell-free virions at a moderate nanomolar concentration by targeting both HIV-1 gp120 and gp41. Moreover, FD028 has broad-spectrum inhibition and inactivation activity against HIV-1 resistant strains and primary isolates of different subtypes without significant cytotoxicity. Therefore, FD028 has potential for further development as an HIV-1 inactivator-based therapeutic.

This study aimed to investigate the knowledge, practices, and attitudes of medical professionals toward Traditional Chinese Medicine (TCM) for the prevention and treatment of coronavirus disease 2019 (COVID-19). All 401 medical professionals were surveyed using an anonymous with an investigator using the Questionnaire star APP. The participants answered 14 questions; of the 401 participants, 55.2% agreed with the statement "TCM can be used for the prevention and treatment of COVID-19," 40.4% remained neutral, and 4.4% disagreed. Moreover, 75.3% agreed with the statement "There is no specific drug for COVID-19," 67% agreed with the statement "TCM can develop immunity to COVID-19" and 62.1% agreed with "TCM can alleviate the symptoms of patients with COVID-19." Meanwhile, 69.1% were aware that TCM has been recommended for COVID-19 by the National Health Commission of the People's Republic of China. Regarding the selection of sources of knowledge on whether "TCM can be used for the prevention and treatment of COVID-19," There were 277, 123, 82, 369, and 17 participants selected sources from "Hospital training," "Academic journals," "Academic Conferences," "Social media platforms (such as WeChat)" and "Others," respectively. Further, 358 participants will take TCM for the prevention of COVID-19. Multiple logistic regression analysis showed that age, major and received TCM treatment within the last five years were independent factors affecting the participants' attitudes. In the absence of specific drugs for COVID-19, more than half of the participants agreed that TCM could be used for the prevention and treatment of COVID-19 and most participants are willing to take TCM to prevent COVID-19, although unsure about its effectiveness. The main information sources on TCM for the treatment and prevention of COVID-19 were social platforms and hospital training.

Algal blooms frequently occur in numerous lakes in China, risking human health and the environment. In contrast, aquatic vegetation contributes to water purification. Due to the similar spectral characteristics shared by algal and aquatic vegetation, both are hardly distinguishable in remote sensing imaging, especially in turbid water bodies. To address this challenge, this study constructed a method to effectively extract algal blooms and aquatic vegetation from the turbid water bodies using Sentinel 2 images with high spatial resolution. Our results showed that the accuracy of the extraction of vegetation information could reach 96.1%. Since this method combined the vegetation extraction results from multiple indices, it effectively tackled the mis-extraction when only the Floating Algae Index (FAI) or the Normalized Difference Vegetation Index (NDVI) is used in water with high turbidity. By combining the image time series information with the natural phenological characteristics of the aquatic vegetation and algal blooms, an improved Vegetation Presence Frequency (VPF) was developed. It effectively distinguished algal blooms and aquatic vegetation without actual measurement data. Based on the above method and process, the information of algal blooms and aquatic vegetation was sufficiently distinguished in five typical lakes in China (Lake Hulun, Lake Hongze, Lake Chaohu, Lake Taihu, and Lake Dianchi), and the spatial distribution was reasonably mapped. The overall identification accuracy of aquatic vegetation and algal blooms using the improved VPF ranged 71.8–84.3%. The spatial transferability test of the method in the independent lakes with the various optical properties indicated the prospects of its application in other turbid water bodies. This study should provide strong methodological and theoretical support for future monitoring of algal blooms in turbid water bodies with vigorous aquatic vegetation, especially in the absence of actual measurement data. This should have practical relevance for water environment management and governance departments.

Our previous studies have shown that cholesterol-conjugated, peptide-based pan-coronavirus (CoV) fusion inhibitors can potently inhibit human CoV infection. However, only palmitic acid (C16)-based lipopeptide drugs have been tested clinically, suggesting that the development of C16-based lipopeptide drugs is feasible. Here, we designed and synthesized a C16-modified pan-CoV fusion inhibitor, EK1-C16, and found that it potently inhibited infection by SARS-CoV-2 and its variants of concern (VOCs), including Omicron, and other human CoVs and bat SARS-related CoVs (SARSr-CoVs). These results suggest that EK1-C16 could be further developed for clinical use to prevent and treat infection by the currently circulating MERS-CoV, SARS-CoV-2 and its VOCs, as well as any future emerging or re-emerging coronaviruses.

The prolonged duration of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has resulted in the continuous emergence of variants of concern (VOC, e.g., Omicron) and variants of interest (VOI, e.g., Lambda). These variants have challenged the protective efficacy of current COVID-19 vaccines, thus calling for the development of novel therapeutics against SARS-CoV-2 and its VOCs. Here, we constructed a novel fusion inhibitor-based recombinant protein, denoted as 5-Helix, consisting of three heptad repeat 1 (HR1) and two heptad repeat 2 (HR2) fragments. The 5-Helix interacted with the HR2 domain of the viral S2 subunit, the most conserved region in spike (S) protein, to block homologous six-helix bundle (6-HB) formation between viral HR1 and HR2 domains and, hence, viral S-mediated cell–cell fusion. The 5-Helix potently inhibited infection by pseudotyped SARS-CoV-2 and its VOCs, including Delta and Omicron variants. The 5-Helix also inhibited infection by authentic SARS-CoV-2 wild-type (nCoV-SH01) strain and its Delta variant. Collectively, our findings suggest that 5-Helix can be further developed as either a therapeutic or prophylactic to treat and prevent infection by SARS-CoV-2 and its variants.

In recent years, infectious diseases caused by viral infections have seriously endangered human health, especially COVID-19, caused by SARS-CoV-2, which continues to spread worldwide. The development of broad-spectrum antiviral inhibitors is urgently needed. Here, we report a series of small-molecule compounds that proved effective against human coronaviruses (HCoV), such as SARS-CoV-2 and its variants of concern (VOCs), including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529), SARS-CoV, MERS-CoV, HCoV-OC43, and other viruses with class I viral fusion proteins, such as influenza virus, Ebola virus (EBOV), Nipah virus (NiV), and Lassa fever virus (LASV). They are also effective against class II enveloped viruses represented by ZIKV and class III enveloped viruses represented by vesicular stomatitis virus (VSV). Further studies have shown that these compounds may exert antiviral effects through a variety of mechanisms, including inhibiting the formation of the six-helix bundle, which is a typical feature of enveloped virus fusion with cell membranes, and/or targeting viral membrane to inactivate cell-free virions. These compounds are expected to become drug candidates against SARS-CoV-2 and other enveloped viruses.

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.

Influenza A viruses (IAV) comprise some of the most common infectious pathogens in humans, and they cause significant mortality and morbidity in immunocompromised people as well as children and the elderly. After screening an FDA-approved drug library containing 1280 compounds by cytopathic effect (CPE) reduction assay using the Cell Counting Kit-8, we found two antihistamines, carbinoxamine maleate (CAM) and S-(+)-chlorpheniramine maleate (SCM) with potent antiviral activity against A/Shanghai/4664T/2013(H7N9) infection with IC50 (half-maximal inhibitory concentration) of 3.56 and 11.84 μM, respectively. Further studies showed that CAM and SCM could also inhibit infection by other influenza A viruses, including A/Shanghai/37T/2009(H1N1), A/Puerto Rico/8/1934(H1N1), A/Guizhou/54/1989(H3N2), and one influenza B virus, B/Shanghai/2017(BY). Mice were challenged intranasally with A/H7N9/4664T/2013 (H7N9) virus and intraperitoneally injected with CAM (10 mg/kg per day) or SCM (1 mg/kg per day) for 5 days. CAM or SCM (10 mg/kg per day) were fully protected against challenge with A/Shanghai/4664T/2013(H7N9). The results from mechanistic studies indicate that both could inhibit influenza virus infection by blocking viral entry into the target cell, the early stage of virus life cycle. However, CAM and SCM neither blocked virus attachment, characteristic of HA activity, nor virus release, characteristic of NA activity. Such data suggest that these two compounds may interfere with the endocytosis process. Thus, we have identified two FDA-approved antihistamine drugs, CAM and SCM, which can be repurposed for inhibiting infection by divergent influenza A strains and one influenza B strain with potential to be used for treatment and prevention of influenza virus infection.

In this paper, the phase transition of titanium slag under microwave heating observed through electron microscopy was systematically investigated. The phase identification and transformation as well as the morphology of samples before and after each treatment were characterized using X-ray powder diffraction (XRD), Fourier-transform infrared spectroscopy, Raman spectroscopy and scanning electron microscopy (SEM). The XRD confirmed that sodium salt roasting could modify the phase composition of titanium slag. The microwave roasting in the presence of sodium salt increased the rutile TiO2 with high crystallinity after acid leaching. The Raman spectroscopy demonstrated the phase transition of titanium slag from anosovite to rutile TiO2 after a series of treatments, and the SEM analyses showed that the surface of calcined products grew plenty of rutile TiO2 with typical characteristics. The results indicate a successful process for an effective and efficient way for the utilization of both titanium slag and preparation of rutile TiO2.

Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple drug-resistant strains has led to the increased failure of ARDs, thus calling for the development of anti-HIV drugs with targets or mechanisms of action different from those of the current ARDs. The first peptide-based HIV entry inhibitor, enfuvirtide, was approved by the U.S. FDA in 2003 for treatment of HIV/AIDS patients who have failed to respond to the current ARDs, which has stimulated the development of several series of protein- and peptide-based HIV entry inhibitors in preclinical and clinical studies. In this review, we highlighted the properties and mechanisms of action for those promising protein- and peptide-based HIV entry inhibitors targeting the HIV-1 gp120 or gp41 and discussed their advantages and disadvantages, compared with the current ARDs.

The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and caused continual outbreaks worldwide with high mortality. However, no effective anti-MERS-CoV drug is currently available. Recently, numerous evolutionary studies have suggested that MERS-CoV originated from bat coronavirus (BatCoV). We herein reported that three peptides derived from the HR2 region in spike protein of BatCoV HKU4, including HKU4-HR2P1, HKU4-HR2P2 and HKU4-HR2P3, could bind the MERS-CoV HR1-derived peptide to form a six-helix bundle (6-HB) with high stability. Moreover, these peptides, particularly HKU4-HR2P2 and HKU4-HR2P3, exhibited potent inhibitory activity against MERS-CoV S-mediated cell–cell fusion and viral infection, suggesting that these HKU4 HR2-derived peptides could be candidates for futher development as antiviral agents against MERS-CoV infection.

Hand, foot, and mouth disease (HFMD), with vesiculae on the hands, feet and mouth, is an infectious disease caused by many viral pathogens. However, the differences of immune response induced by these pathogens are unclear. We compared the clinical manifestations and the levels of immunologic indicators from 60 HFMD patients caused by different viral pathogens to analyze the differences in the immune response. It was shown that Th2 cytokines (IL-4 and IL-10) increased significantly in EV71-infected children; Th1 cytokines (IL-2 and IFN-γ) rose in CA16-infected children; both Th1 and Th2 cytokines elevated in non-EVG-infected children; only individual cytokines (such as IL-10) went up in EVG-infected children. Meanwhile, the antibodies induced by viral infection could not cross-interfere between the different pathogens. These differences might be due to variations in the immune response induced by the individual pathogens or to the pathogenesis of the infections by the individual pathogens.

Storage of cellular triacylglycerols (TAGs) in lipid droplets (LDs) has been linked to the progression of many metabolic diseases in humans, and to the development of biofuels from plants and microorganisms. However, the biogenesis and dynamics of LDs are poorly understood. Compared with other organisms, bacteria seem to be a better model system for studying LD biology, because they are relatively simple and are highly efficient in converting biomass to TAG. We obtained highly purified LDs from Rhodococcus sp. RHA1, a bacterium that can produce TAG from many carbon sources, and then comprehensively characterized the LD proteome. Of the 228 LD-associated proteins identified, two major proteins, ro02104 and PspA, constituted about 15% of the total LD protein. The structure predicted for ro02104 resembles that of apolipoproteins, the structural proteins of plasma lipoproteins in mammals. Deletion of ro02104 resulted in the formation of supersized LDs, indicating that ro02104 plays a critical role in cellular LD dynamics. The putative α helix of the ro02104 LD-targeting domain (amino acids 83–146) is also similar to that of apolipoproteins. We report the identification of 228 proteins in the proteome of prokaryotic LDs, identify a putative structural protein of this organelle, and suggest that apolipoproteins may have an evolutionarily conserved role in the storage and trafficking of neutral lipids.

Abstract Chronic exposure to saturated fatty acids can cause insulin resistance. However, the acute effects of fatty acids are not clear and need to be elucidated because plasma fatty acid concentrations fluctuate postprandially. Here, we present the acute effects of palmitate (PA) on skeletal muscle cells and their underlying molecular mechanisms. Immuno­fluorescence results showed that PA rapidly induced GLUT4 translocation and stimulated glucose uptake in rat skeletal muscle cell line L6. Phosphorylation of AMP-activated protein kinase (AMPK), Akt, and extracellular signal-related kinase1/2 (ERK1/2) was enhanced by PA in a time-dependent manner. Cell surface-bound PA was sufficient to stimulate Akt phosphorylation. The inhibitors of PI3 kinase (PI3K), AMPK, Akt, and ERK1/2 could decrease PA-induced glucose uptake, and PI3K inhibitor decreased AMPK, Akt, and ERK1/2 phosphorylation. Weakening AMPK activity reduced phosphorylation of Akt but not ERK1/2, and Akt inhibitor could not affect ERK1/2 activation either. Meanwhile, ERK1/2 inhibitors had no effect on Akt phosphorylation. Taken together, our data suggest that PA-mediated glucose uptake in skeletal muscle cells may be stimulated by the binding of PA to cell surface and followed by PI3K/AMPK/Akt and PI3K/ERK1/2 pathways independently.

Enterovirus 71 (EV71) is the major pathogen responsible for fatal hand, foot and mouth disease (HFMD). Our previous work reported on an EV71-infected rhesus monkey infant model that presented with histo-pathologic changes of the central nervous system (CNS) and lungs. This study is focused on the correlated modulation of gene expression in the peripheral blood mononuclear cells (PBMCs) from EV71-infected rhesus monkey infants. The expression of more than 500 functional genes associated with multiple pathways was modulated. The expression of genes associated with immune inflammatory responses was up-regulated during the period from days 4 to 10 post-infection. The expression of two genes (TAC1 and IL17A), which play major roles in inflammatory reactions, was remarkably up-regulated during the infection period. Furthermore, a higher expression level of the TAC1 gene was identified in the CNS compared to the lungs, but a high expression level of the IL-17A gene was observed in the lungs and not in the CNS. The results of this study suggest at least two facts about EV71 infection, which are that: the TAC1 gene that encodes substance P and neurokinin-A is present in both PBMCs and the hypothalamus; and the up-regulation of IL-17A is sustained in the peripheral blood.

Enterovirus 71 (EV71), a major causative agent of hand-foot-and-mouth disease (HFMD), causes outbreaks among children in the Asia-Pacific region. A vaccine is urgently needed. Based on successful pre-clinical work, phase I and II clinical trials of an inactivated EV71 vaccine, which included the participants of 288 and 660 respectively, have been conducted. In the present study, the immune response and the correlated modulation of gene expression in the peripheral blood mononuclear cells (PBMCs) of 30 infants (6 to 11 months) immunized with this vaccine or placebo and consented to join this study in the phase II clinical trial were analyzed. The results showed significantly greater neutralizing antibody and specific T cell responses in vaccine group after two inoculations on days 0 and 28. Additionally, more than 600 functional genes that were up- or down-regulated in PBMCs were identified by the microarray assay, and these genes included 68 genes associated with the immune response in vaccine group. These results emphasize the gene expression profile of the immune system in response to an inactivated EV71 vaccine in humans and confirmed that such an immune response was generated as the result of the positive mobilization of the immune system. Furthermore, the immune response was not accompanied by the development of a remarkable inflammatory response.NCT01391494 and NCT01512706.

Brown millet and millet bran are rich in nutrients. After stabilization treatment, they are easy to store and transport. However, it is difficult for them to be accepted as food ingredients by consumers due to their poor texture and taste. Micronization can alter chemical and functional properties of materials, potentially improving quality of brown millet and millet bran, as well as their taste. This study investigated the effects of micronization on morphology attributes (particle size distribution, microstructure and color), functional attributes (oil binding capacity, water binding capacity, water solubility index, swelling capacity and bulk density), and digestion and release of free polyphenols and flavonoids in fresh and radio frequency (RF) stabilized brown millet and millet bran. The results showed that micronization treatment effectively reduced particle size of the samples, increased particle surface area, significantly improved powder color, and affected their microstructure. Micronization treatment also increased bulk density of brown millet and millet bran. When the particle size was reduced to pass through a 150-mesh sieve, the bulk density of fresh and RF stabilized brown millet and millet bran increased by 13.68%, 38.77% and 22.50%, 25.33%, respectively. Micronization reduced oil binding capacity and water binding capacity of the samples, and both indicators continuously decreased with the decline of particle size. Micronization also improved the release of antioxidant substances (free polyphenols and free flavonoids) from brown millet and millet bran. When digestion for 120 min, the release of free flavonoids in intestine of 150-mesh fresh brown millet powder increased by 70.89% compared with 50-mesh powder, and the release of free polyphenols in stomach increased by 12.22%. This study indicates that micronization can improve functional and nutritional attributes of brown millet and millet bran, offering valuable reference and guidance for the development of micronized raw materials from brown millet and millet bran. [ABSTRACT FROM AUTHOR]