Fabrication of dry S/O/W microcapsule and its probiotic protection against different stresses.

BACKGROUND: Encapsulation is commonly used to protect probiotics against harsh stresses. Thus, the fabrication of microcapsules with special structure is critical. In this work, microcapsules with the structure of S/O/W (solid-in-oil-in-water) emulsion were prepared for probiotics, with butterfat containing probiotics as the inner core and with whey protein isolate fibrils (WPIF) and antioxidants (epigallocatechin gallate, EGCG; glutathione, GSH) as the outer shell. RESULTS: Based on the high viscosity and good emulsifying ability of WPIF, dry well-dispersed microcapsules were successfully prepared via the stabilization of the butterfat emulsion during freeze-drying with 30-50 g L-1 WPIF. WPIF, WPIF + EGCG, and WPIF + GSH microcapsules with 50 g L-1 WPIF protected probiotics very well against different stresses and exhibited similar inactivation results, indicating that EGCG and GSH exerted neither harm or protection on probiotics. This significantly reduced the harmful effects of antioxidants on probiotics. Almost all the probiotics survived after pasteurization, which was critical for the use of probiotics in other foods. The inactivation values of probiotics in microcapsules were around 1 log in simulated gastric juice (SGJ), about 0.5 log in simulated intestinal juice (SIJ), and around 1 log after 40 days of ambient storage. CONCLUSION: Dry S/O/W microcapsule, with butterfat containing probiotics as the inner core and WPIF as the outer shell, significantly increased the resistance of probiotics to harsh environments. This work proposed a preparation method of dry S/O/W microcapsule with core/shell structure, which could be used in the encapsulation of probiotics and other bioactive ingredients.

Effect of emulsifiers on the properties of corn starch films incorporated with Zanthoxylum bungeanum essential oil.

The use of natural and safe ingredients in green food packaging material is a hot research topic. This study investigated the effect of different emulsifiers on starch film properties. Three types of emulsifiers, including Tween 80 as a small-molecule surfactant, sodium caseinate (CAS), whey protein isolate (WPI), and gelatin (GE) as macromolecule emulsifiers, whey protein isolate fibril (WPIF) as a particle emulsifier, were utilized to prepare Zanthoxylum bungeanum essential oil (ZBO) emulsions. The mechanical, physical, thermal, antibacterial properties, microstructure and essential oil release of starch films were investigated. CAS-ZBO nanoemulsion exhibited the smallest particle size of 198.6 ± 2.2 nm. The film properties changed with different emulsifiers. CAS-ZBO film showed the highest tensile strength value. CAS-ZBO and WPIF-ZBO films exhibited lower water vapor permeability than Tween-ZBO. CAS-ZBO film showed good dispersion of essential oil, the slowest release rate of essential oils in all food simulants, and the best antibacterial effect against Staphylococcus aureus and Listeria monocytogenes. The films composed of CAS-ZBO nanoemulsion, corn starch, and glycerol are considered more suitable for food packaging. This work indicated that natural macromolecule emulsifiers of CAS and WPIF are expected to be used in green food packaging material to offer better film properties.

Valuation of EQ-5D-5L health states from cancer patients' perspective: a feasibility study.

OBJECTIVES: To assess the feasibility of estimating an EQ-5D-5L value set using a small study design in cancer patients and to compare the EQ-5D-5L values based on the preferences of cancer patients with those of the general public. METHODS: Patients with clinically diagnosed cancers were recruited from two hospitals in Shanghai, China. In face-to-face interviews using the EQ-PVT survey, health states were valued by cancer patients using both cTTO and DCE methods. cTTO data was modelled alone or jointly with DCE data. Forty-eight models using different model specifications (cross-attribute level effect [CALE] and additive models), random/fixed effects model assumptions, data heteroscedasticity and censoring were estimated. The best performed model was identified in terms of monotonicity of estimated model coefficients and out-of-sample prediction accuracy. RESULTS: Data collected from 221 cancer patients who participated in the study were included. The hybrid CALE model using both TTO and DCE data performed best in terms of prediction accuracy (Lin's concordance coefficient = 0.989; root mean squared error = 0.058) and suggested that pain/discomfort and anxiety/depression were the most undesirable health problems. Compared to values based on general Chinese public's health preferences, the values based on cancer patients' preferences were much higher and lower for health states characterized by extreme mobility problems and severe/extreme pain or discomfort, respectively. CONCLUSION: This study demonstrated the feasibility of using a small design to develop EQ-5D-5L value sets based on cancer patients' health preferences. Since there were signs of differences between preferences of patients and general population, it may be valuable to develop patient-specific value sets and use them in clinical decision making and economic evaluations.

Preparation and application of an imidazolium-based poly (ionic liquid) functionalized silica sorbent for solid-phase extraction of parabens from food samples.

In this work, an imidazolium-based poly (ionic liquid) (poly(1-octyl-3-vinyl- imidazolium naphthalene sulfonate)) functionalized silica (poly(C8VIm+NapSO3-) @SiO2) was successfully prepared for the determination of parabens in food samples. The prepared poly(C8VIm+NapSO3-)@SiO2 was characterized by Fourier transform infrared spectrometry (FT-IR), X-ray photoelectron spectrogram (XPS) and Scanning electron microscopy (SEM). The simulation calculation results indicated that the suitable binding energies were between the polymeric ionic liquids and parabens, and the main interactions for extraction were hydrogen bonding, electrostatic and π-π stacking interactions. In addition, compared with commercial extraction materials, the prepared poly(C8VIm+NapSO3-)@SiO2 sorbent showed comparable or even better extraction performance towards parabens. The effective parameters were optimized by a combination of the univariate method and Box-Behnken design (BBD). Under the optimum conditions, coupled with high performance liquid chromatography (HPLC), wide linear ranges (1.0-800 µg L-1), good linearity (R2 ≥ 0.9997) and low limits of detection (0.1 µg L-1) were obtained. In addition, the intra-day and inter-day relative standard deviations (RSDs) were all lower than 6.3%. Moreover, the proposed method was successfully used for the determination of parabens in food samples and satisfactory recoveries in the range of 76.9-97.4% were obtained. The results indicated that the proposed method had good sensitivity, accuracy and precision for the detection of parabens in food samples.

Starch/polyvinyl alcohol with ionic liquid/graphene oxide enabled highly tough, conductive and freezing-resistance hydrogels for multimodal wearable sensors.

With ever-growing demand for eco-friendly materials for wearable electronics, biopolymer-based hydrogels have drawn significant attention. As one of the most abundant and biodegradable biopolymers, starch-based hydrogels have a great potential for wearable electronics. However, mechanical fragility, low conductivity and subzero freeze restrict their applications. Here, a multifunctional hydrogel was facilely fabricated by integrating ionic liquid and graphene oxide into potato starch/polyvinyl alcohol skeleton via a green physical-crosslinking method. The abundant hydrogen-bond and electrostatic interactions endowed the hydrogel with excellent stretchability (657.5 %), strength (0.64 MPa), high conductivity (1.98 S·m-1) and good anti-freezing property (< -20 °C). Multiple characterizations and theoretical simulation (DFT) were combined to understand and confirm the interactions among different components. Taking advantage of these properties, multimodal wearable sensors were constructed for sensing tension (gauge factor: 6.04), compression (gauge factor: 3.27) and temperature (sensitivity: 0.71 %/°C), which are applied for monitoring human motion, daily-life pressure and body temperature. The sensor had a good anti-fatigue property with stable signals during 2000 cycles. Moreover, the sensor can effectively recognize handwriting and perform human-computer interaction. This work provides a promising route to develop sustainable and multifunctional biopolymer hydrogels for wearable sensors with versatile applications in human health, exercise monitors and soft robots.

Characteristics of health-state utilities used in cost-effectiveness analyses: a systematic review of published studies in Asia.

INTRODUCTION: Cost-utility analysis (CUA) is the preferred form of economic evaluation in many countries. As one of the key data inputs in cost-utility models, health state utility (HSU) has a crucial impact on CUA results. In the past decades, health technology assessment has been expanding rapidly in Asia, yet research examining the methodology and process used to generate cost-effectiveness evidence is scarce. The aim of this study was to examine the reporting of the characteristics of HSU data used in CUAs in Asia and how the characteristics have changed over time. METHODS: A systematic literature search was performed to identify published CUA studies targeting Asian populations. Information was extracted for both the general characteristics of selected studies and the characteristics of reported HSU data. For each HSU value identified, we extracted data for four key characteristics, including 1) estimation method; 2) source of health-related quality of life (HRQoL) data; 3) source of preference data; and 4) sample size. The percentage of nonreporting was calculated and compared over two time periods (1990-2010 vs 2011-2020). RESULTS: A total of 789 studies were included and 4,052 HSUs were identified. Of these HSUs, 3,351 (82.7%) were from published literature and 656 (16.2%) were from unpublished empirical data. Overall, the characteristics of HSU data were not reported in more than 80% of the studies. Of HSUs whose characteristics were reported, most of them were estimated using the EQ-5D (55.7%), Asian HRQoL data (91.9%), and Asian health preferences (87.7%); 45.7% of the HSUs was estimated with a sample of 100 or more individuals. All four characteristics showed improvements after 2010. CONCLUSION: Over the past two decades, there has been a significant increase in CUA studies targeting Asian populations. However, HSU's characteristics were not reported in most of the CUA studies, making it difficult to evaluate the quality and appropriateness of the HSUs used in those cost-effectiveness studies.

Cost-effectiveness of sacituzumab govitecan versus chemotherapy in advanced or metastatic triple-negative breast cancer.

PURPOSE: The ASCENT trial demonstrated the efficacy of sacituzumab govitecan for the treatment of advanced or metastatic triple-negative breast cancer (TNBC). The current study evaluated the cost-effectiveness of receiving sacituzumab govitecan compared with standard of care chemotherapy from the United States payer perspective. METHODS: A partitioned survival approach was used to project the disease course of advanced or metastatic TNBC. Two survival modes were applied to analyze two groups of patients. The survival data were gathered from the ASCENT trial. Direct medical costs were derived from the data of Centers for Medicare & Medicaid Services. Utility data was collected from the published literature. The incremental cost-utility ratio (ICUR) was the primary outcome that measured the cost-effectiveness of therapy regimen. One-way sensitivity and probabilistic sensitivity analysis were implemented to explore the uncertainty and validate the stability of results. RESULTS: In the base-case, the ICUR of sacituzumab govitecan versus chemotherapy is $ 778,771.9/QALY and $ 702,281/QALY for full population group and brain metastatic-negative (BMN) group with the setting of classic survival mode. And in the setting of cure survival mode, the ICUR is $ 506,504.5/QALY for the full population group and $ 274,232.0/QALY for BMN population group. One-way sensitivity analyses revealed that the unit cost of sacituzumab govitecan and body weight were key roles that lower the ICUR value. Probabilistic sensitivity analyses also showed that reducing the unit price of sacituzumab govitecan can improve the likelihood of becoming cost-effective. CONCLUSION: The cost-effectiveness analysis suggested that from a US payer perspective, sacituzumab govitecan at current price is unlikely to be a preferred option for patients with advanced or metastatic TNBC at a threshold of $ 150,000/QALY.

Effects of Drying Methods on Taste Components and Flavor Characterization of Cordyceps militaris.

The influences of four drying methods (hot air drying (HAD), vacuum freeze drying (VFD), vacuum drying (VD) and intermittent microwave combined with hot air drying (MW-HAD)) on the taste profile and flavor characteristic of Cordyceps militaris were investigated. MW-HAD samples had the highest levels of umami taste 5'-nucleotides, bitter taste amino acids, and equivalent umami concentration (EUC) value. The aroma fingerprints and differences of dried Cordyceps militaris were established by GC-MS with odor activity values (OAVs) and GC-IMS with principal component analysis (PCA). GC-MS data showed that the predominant volatiles of dried samples were aldehydes, alcohols, and ketones. VFD samples had the highest amount of total aroma compounds and C8 compounds. Moreover, 21 aroma-active components (OAVs ≥ 1) were the main contributors to the flavor of dried Cordyceps militaris. The OAVs of 1-octen-3-one and 3-octanone associated with mushroom-like odor in VFD were significantly higher than other samples. Furthermore, a significant difference in flavor compounds of four dried samples was also clearly demonstrated by GC-IMS analysis with PCA. GC-IMS analysis revealed that VFD samples had the most abundant flavor compounds. Overall, MW-HAD was an effective drying method to promote umami taste, and VFD could superiorly preserve volatiles and characteristic aroma compounds in dried Cordyceps militaris.

Atezolizumab plus platinum-based chemotherapy as first-line therapy for metastatic urothelial cancer: A cost-effectiveness analysis.

Purpose: According to the IMvigor130 trial, adding atezolizumab to platinum-based chemotherapy was effective in the treatment of metastatic urothelial cancer (mUC). Based on the perspective of the United States and China, the current study evaluated cost-effectiveness of atezolizumab plus chemotherapy for mUC patients in the first-line setting. Methods: A partitioned survival model was adopted for mUC patients. The survival data were derived from the IMvigor130 trial. Direct cost values were collected from the Centers for Medicare and Medicaid Services (CMS), Chinese Drug Bidding Database, and published literatures. The utility and toxicity data were gathered from related research studies and IMvigor130 trial. The incremental cost-utility ratios (ICURs) and incremental cost-effectiveness ratios (ICERs) were calculated and analyzed. Scenario analyses and sensitivity analyses were performed to observe the outputs and uncertainties. Results: The base-case analysis showed that the ICUR of atezolizumab plus chemotherapy versus chemotherapy in American and Chinese settings is $ 737,371 /QALY and $ 385,384 /QALY, respectively. One-way sensitivity analyses showed that the ICUR ranged from $ 555,372/QALY to $ 828,205/QALY for the United States. Also, the range was from $ 303,099/QALY to $ 433,849/QALY in the Chinese setting. A probabilistic sensitivity analysis showed the likelihood that atezolizumab plus chemotherapy becoming the preferred strategy was a little low even if the price reduction strategy was applied. Conclusion: Adding atezolizumab to chemotherapy improved survival time, but it is not a cost-saving option compared to chemotherapy for metastatic urothelial cancer patients in the American and Chinese settings.

Budget Impact Analysis of the Introduction of a Trastuzumab Biosimilar for HER2-Positive Breast Cancer in China.

BACKGROUND AND OBJECTIVE: Biosimilars provide the possibility to reduce the high expenditure on biologic drugs and expand access to effective but less expensive treatments. Biosimilars of trastuzumab showed significant cost savings from the payer's perspective in the USA and Europe. After 2020, with the first approval of a trastuzumab biosimilar in China, it became feasible for biosimilar switching for trastuzumab. However, the economic impact of switching to a trastuzumab biosimilar was not evaluated. A budget impact model was constructed from a payer's perspective of China to demonstrate the economic impact of the introduction of a biosimilar trastuzumab in the treatment of human epidermal growth factor receptor 2-positive breast cancer. METHODS: This budget impact model was based on disease incidence to estimate the net budget impact using epidemiological data from the literature, financial reports from manufacturers on the market shares of originator trastuzumab (Herceptin®) or the biosimilar, and localized direct costs. The budget impact was estimated for 5 years after the introduction of the first-approved trastuzumab biosimilar in China. Furthermore, two scenarios were simulated in this study to estimate the budget impact of biosimilars within: (1) real-world practice and (2) the policy of volume-based procurement. RESULTS: Analyses of the base-case and scenario results implied that adoption of a trastuzumab biosimilar would lead to an expenditure decrease. The average total cost savings over 5 years was estimated to be US$46,651,348, with a range from $10,306,611 in year 1 to $60,821,822 in year 5. The cost savings could benefit an additional 654-3858 patients with breast cancer. If utilizing costs from real-world practice, the introduction of a trastuzumab biosimilar could help an additional 2237-13,203 patients get access to human epidermal growth factor receptor 2-positive targeted therapy. When volume-based procurement was carried out after year 4, $672,366,180 could be saved annually. CONCLUSIONS: This budget impact analysis emphasized the positive effects of adopting a trastuzumab biosimilar in the healthcare system of China. However, cost savings still have a large potential to decrease by regulating pricing and by the procurement policy of biosimilars.

Melatonin Attenuates the Urea-Induced Yields Improvement Through Remodeling Transcriptome and Rhizosphere Microbial Community Structure in Soybean.

Foliar application of nitrogen to enhance crop productivity has been widely used. Melatonin is an effective regulator in promoting plant growth. However, the effects of melatonin and the combination of melatonin and nitrogen on soybeans yields production remain largely unknown. In this study, a field experiment was conducted to evaluate the effects and mechanisms of spraying leaves with melatonin and urea on soybeans. Foliar application of urea significantly increased soybean yields and melatonin did not affect the yields, while combination of melatonin and urea significantly reduced the yields compared to the application of urea alone. A leaf transcriptional profile was then carried out to reveal the underlying mechanism and found that foliar spraying of urea specifically induced the expression of genes related to amino acid transport and nitrogen metabolism. However, foliar application of melatonin significantly changed the transcriptional pattern established by urea application and increased the expression of genes related to abiotic stress signaling pathways. The effects of melatonin and urea treatment on soil microbiome were also investigated. Neither melatonin nor urea application altered the soil microbial alpha diversity, but melatonin application changed rhizosphere microbial community structure, whereas the combination of melatonin and urea did not. Melatonin or urea application altered the abundance of certain taxa. The number of taxa changed by melatonin treatment was higher than urea treatment. Collectively, our results provide new and valuable insights into the effects of foliar application of melatonin to urea and further show that melatonin exerts strong antagonistic effects on urea-induced soybean yields, gene expression and certain soil microorganisms.

Improving the sensitivity of lateral flow immunoassay for Salmonella typhimurium detection via flow-rate regulation.

Application of the traditional immunochromatographic assay (ICGA) has been limited by its poor sensitivity. The objective of this study was to increase the sensitivity of the traditional ICGA. A dual-mode ICGA (D-M ICGA) was developed by combining a nanozyme-assisted signal-amplification strategy with a magnetic-nanoparticle-based flow-speed-control strategy. Salmonella typhimurium can be detected simultaneously based on color and magnetic signals in the detection area of the D-M ICGA strip. The calculated limits of detection of 50 cfu·mL-1 and 75 cfu·mL-1 in the color and magnetic modes, respectively, were approximately 1000 times lower than those of the traditional ICGA. The selectivity and practical applicability of the D-M ICGA were also confirmed in this study. The results prove that the D-M ICGA is an assay that could be used for Salmonella typhimurium detection and can be easily adapted to detect other pathogenic bacteria.

Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway.

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: ß-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A1; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.

Differential light-dependent regulation of soybean nodulation by papilionoid-specific HY5 homologs.

Legumes have evolved photosynthesis and symbiotic nitrogen fixation for the acquisition of energy and nitrogen nutrients. During the transition from heterotrophic to autotrophic growth, blue light primarily triggers photosynthesis and low soil nitrogen induces symbiotic nodulation. Whether and how darkness and blue light influence root symbiotic nodulation during this transition is unknown. Here, we show that short-term darkness promotes nodulation and that blue light inhibits nodulation through two soybean TGACG-motif-binding factors (STF1 and STF2), which are Papilionoideae-specific transcription factors and divergent orthologs of Arabidopsis ELONGATED HYPOCOTYL 5 (HY5). STF1 and STF2 negatively regulate soybean nodulation by repressing the transcription of nodule inception a (GmNINa), which is a central regulator of nodulation, in response to darkness and blue light. STF1 and STF2 are not capable of moving from the shoots to roots, and they act both locally and systemically to mediate darkness- and blue-light-regulated nodulation. We further show that cryptochromes GmCRY1s are required for nodulation in the dark and partially contribute to the blue light inhibition of nodulation. In addition, root GmCRY1s mediate blue-light-induced transcription of STF1 and STF2, and intriguingly, GmCRY1b can interact with STF1 and STF2 to stabilize the protein stability of STF1 and STF2. Our results establish that the blue light receptor GmCRY1s-STF1/2 module plays a pivotal role in integrating darkness/blue light and nodulation signals. Furthermore, our findings reveal a molecular basis by which photosensory pathways modulate nodulation and autotrophic growth through an intricate interplay facilitating seedling establishment in response to low nitrogen and light signals.

HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity.

HIV-1-negative factor (Nef) protein antagonizes serine incorporator 5 (SERINC5) by redirecting this potent restriction factor to the endosomes and lysosomes for degradation. However, the precise mechanism remains unclear. Using affinity purification/mass spectrometry, we identify cyclin K (CycK) and cyclin-dependent kinase 13 (CDK13) as a Nef-associated kinase complex. CycK/CDK13 phosphorylates the serine at position 360 (S360) in SERINC5, which is required for Nef downregulation of SERINC5 from the cell surface and its counteractivity of the SERINC5 antiviral activity. To understand the role of S360 phosphorylation, we generate chimeric proteins between CD8 and SERINC5 to study their response to Nef. Nef not only downregulates but, importantly, also binds to this chimera in an S360-dependent manner. Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery.

Trimer-based aptasensor for simultaneous determination of multiple mycotoxins using SERS and fluorimetry.

An aptasensor is reported for the detection of three different kinds of mycotoxins, i.e., zearalenone (ZEN), ochratoxin A (OTA), and fumonisin B1 (FB1). Based on fluorescence resonance energy transfer effect (FRET) and surface-enhanced Raman scattering (SERS), the levels of ZEN, FB1, and OTA can be simultaneously determined. Under 980-nm and 650-nm laser excitation, the logarithmic values of fluorescence signal intensities at 543 nm and 670 nm are slowly increased as the concentrations of ZEN and OTA vary from 0.1 ng mL-1 and 0.05 ng mL-1 to 100 ng mL-1 and 25 ng mL-1, respectively. For FB1, under 980-nm laser excitation, the logarithmic value of SERS signal intensity at 1567 cm-1 gradually increases with the concentration of FB1 in the range 0.05-200 pg mL-1 (R2 = 0.996). The detection limits of the proposed assay for ZEN, OTA, and FB1 are 0.03 ng mL-1, 0.01 ng mL-1, and 0.02 pg mL-1, respectively. The selectivity experiment results indicate this assay possesses a high selectivity over other commonly encountered mycotoxins. The average recoveries range from 90 to 107%, revealing satisfactory application potential of the proposed assay. The developed aptasensor will bring bright prospects for research in the field of multiplexed mycotoxine detection. Graphical Abstract Schematic representation of an aptamer-based assay for multiple mycotoxins determination.

Economic burden of patients with advanced non-small-cell lung cancer receiving nivolumab versus chemotherapy in China.

Aim: As new treatment patterns are gradually being used in patients with non-small-cell lung cancer, it is necessary to have a better understanding of real-world data on clinical practices and their potential impact on healthcare resource utilization (HCRU). Patients & methods: A retrospective observational study was conducted with electronic medical records from Shanghai Chest Hospital. Hospitalized patients treated with nivolumab or second-line chemotherapy were included. Results: A total of 296 patients were included in this study, of whom 187 were treated with nivolumab. About 74.33% received nivolumab monotherapy at different doses. The mean cost of nivolumab was $3334.14 (±86.69). Nivolumab decreased inpatient days to 1.9545 days with a more stable cost and HCRU per cycle. Conclusion: Nivolumab is expensive but it reduces other HCRU.

The Differences in the Safety and Tolerability of Immune Checkpoint Inhibitors as Treatment for Non-Small Cell Lung Cancer and Melanoma: Network Meta-Analysis and Systematic Review.

Background: Immune checkpoint inhibitors (ICIs) have evolved for the treatment of solid tumors. In addition to the efficacy of ICIs for cancer, the adverse events (AEs) of ICIs are also noteworthy for gradually more extensive clinical use. Objective: To conduct a systematic review and network meta-analysis to evaluate the treatment-related AEs that occurred in clinical trials using different kinds of ICIs, to explore the differences in AEs among ICIs for treating non-small cell lung cancer (NSCLC) and melanoma, and to compare select immune-related AEs. Methods: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and other available sources were systematically searched for published reports up to January 1, 2019. Two reviewers independently selected reports about phase II/III randomized controlled trials to compare among ICIs and between ICIs and chemotherapy. After the bias assessment of all included trials, a Bayesian network meta-analysis was performed. The primary outcomes were any-grade and high-grade treatment-related AEs from all ICIs. The secondary outcomes were AEs in patients with NSCLC and melanoma and the presence of the select AEs pneumonitis/pneumonia and colitis. Results: Eighteen randomized controlled trials containing 11,223 patients with NSCLC or melanoma were included. A total network meta-analysis was conducted. The meta-analysis showed that atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were generally more tolerable than other ICIs. ICI combined with chemotherapy might suggest a higher risk of treatment-related AEs than monotherapy with a single ICI, except durvalumab and ipilimumab. In the NSCLC subgroup, pembrolizumab was associated with a higher risk of high-grade AEs than nivolumab. In addition, ICIs (nivolumab, atezolizumab, and avelumab) led to a lower risk of any/high-grade treatment-related AEs than traditional chemotherapy and ICI combination chemotherapy. However, ICIs did not present preferable safety and tolerability compared to chemotherapy in treating melanoma. Compared with chemotherapy, nivolumab, durvalumab, two ICIs, and ICI combined chemotherapy led to more pneumonitis/pneumonia. However, when treating NSCLC, different types of ICIs did not differ significantly regarding the incidence of pneumonitis/pneumonia. A combination of nivolumab and ipilimumab had the highest risk for colitis, while pembrolizumab and atezolizumab had a lower possibility than the other ICIs. Conclusion: Atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were ordinarily safer than other ICIs. When treating NSCLC, nivolumab had the lowest risk; when treating melanoma, pembrolizumab had the lowest toxicity.

Antiviral activity of Piscidin 1 against pseudorabies virus both in vitro and in vivo.

BACKGROUND: Swine-origin virus infection spreading widely could cause significant economic loss to porcine industry. Novel antiviral agents need to be developed to control this situation. METHODS: In this study, we evaluated the activities of five broad-spectrum antimicrobial peptides (AMPs) against several important swine-origin pathogenic viruses by TCID50 assay. Plaque reduction assay and cell apoptosis assay were also used to test the activity of the peptides. Protection effect of piscidin against pseudorabies virus (PRV) was also examined in mouse model. RESULTS: Piscidin (piscidin 1), caerin (caerin 1.1) and maculatin (maculatin 1.1) could inhibit PRV by direct interaction with the virus particles in a dose-dependent manner and they could also protect the cells from PRV-induced apoptosis. Among the peptides tested, piscidin showed the strongest activity against PRV. Moreover, in vivo assay showed that piscidin can reduce the mortality of mice infected with PRV. CONCLUSION: In vitro and in vivo experiments indicate that piscidin has antiviral activity against PRV.

CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5.

Serine incorporator 5 (SERINC5) is a recently identified restriction factor that strongly blocks HIV-1 entry but is counteracted by Nef. Notably, tier 1 HIV-1 Env proteins are sensitive to SERINC5, whereas the majority of tier 2/3 Env proteins are resistant to SERINC5, when viruses are produced from CD4-negative cells and tested by a single-round replication assay. Here, we investigated the Env-dependent SERINC5 antiviral mechanism by comparing tier 1 NL Env with tier 3 AD8 Env proteins. We found that when NL and AD8 viruses were inoculated into CD4+ T cells and human peripheral blood mononuclear cells (PBMCs), the propagation of the two viruses was restricted to a similar level when Nef was not expressed. Using a bimolecular fluorescence complementation (BiFC) assay, we detected Env-Env association and Env-SERINC5 interactions. A much greater level of NL Env-SERINC5 interactions was detected than was AD8 Env-SERINC5 interactions, which was further validated by immunoprecipitation assays. In addition, SERINC5 dissociated the NL Env trimeric complex more effectively than the AD8 Env trimeric complex when CD4 was not expressed. However, when CD4 was expressed, SERINC5 became more capable of interacting with AD8 Env and dissociating its trimeric complex. Moreover, AD8 and several other tier 2/3 viruses produced in the presence of CD4 became sensitive to SERINC5 when measured by the single-round replication assay. Because tier 1 and tier 2/3 Env trimers have open and closed conformations, respectively, and CD4 opens the closed conformation, we conclude that SERINC5 selectively dissociates Env trimers with an open conformation to restrict HIV-1 replication.IMPORTANCE Restriction factors provide the first line of defense against retrovirus infection by posing several blocks to the viral replication cycle. SERINC5 is a novel restriction factor that strongly blocks HIV-1 entry, although it is counteracted by Nef. Currently, it is still unclear how HIV-1 entry is blocked by SERINC5. Notably, this entry block is dependent on viral Env proteins. Laboratory-adapted HIV-1 strains are sensitive, whereas primary isolates are highly resistant to SERINC5. Env proteins mediate virus entry via extensive conformational rearrangements from a closed ground state to a CD4-bound open state. We detected Env-Env associations and Env-SERINC5 interactions in live cells by a novel bimolecular fluorescence assay. We demonstrate that CD4 expression increases the Env sensitivity to SERINC5 and allows SERINC5 to dissociate the Env complex, suggesting that SERINC5 restriction is dependent on Env conformation. Our results provide new insights into the poorly defined Env-dependent SERINC5 antiviral mechanism.