COVID-19 vaccines based on viral nanoparticles displaying a conserved B-cell epitope show potent immunogenicity and a long-lasting antibody response

The COVID-19 pandemic caused by SARS-CoV-2 sparked intensive research into the development of effective vaccines, 50 of which have been approved thus far, including the novel mRNA-based vaccines developed by Pfizer and Moderna. Although limiting the severity of the disease, the mRNA-based vaccines presented drawbacks, such as the cold chain requirement. Moreover, antibody levels generated by these vaccines decline significantly after 6 months. These vaccines deliver mRNA encoding the full-length spike (S) glycoprotein of SARS-CoV-2, but must be updated as new strains and variants of concern emerge, creating a demand for adjusted formulations and booster campaigns. To overcome these challenges, we have developed COVID-19 vaccine candidates based on the highly conserved SARS CoV-2, 809-826 B-cell peptide epitope (denoted 826) conjugated to cowpea mosaic virus (CPMV) nanoparticles and bacteriophage Qβ virus-like particles, both platforms have exceptional thermal stability and facilitate epitope delivery with inbuilt adjuvant activity. We evaluated two administration methods: subcutaneous injection and an implantable polymeric scaffold. Mice received a prime–boost regimen of 100 μg per dose (2 weeks apart) or a single dose of 200 μg administered as a liquid formulation, or a polymer implant. Antibody titers were evaluated longitudinally over 50 weeks. The vaccine candidates generally elicited an early Th2-biased immune response, which stimulates the production of SARS-CoV-2 neutralizing antibodies, followed by a switch to a Th1-biased response for most formulations. Exceptionally, vaccine candidate 826-CPMV (administered as prime-boost, soluble injection) elicited a balanced Th1/Th2 immune response, which is necessary to prevent pulmonary immunopathology associated with Th2 bias extremes. While the Qβ-based vaccine elicited overall higher antibody titers, the CPMV-induced antibodies had higher avidity. Regardless of the administration route and formulation, our vaccine candidates maintained high antibody titers for more than 50 weeks, confirming a potent and durable immune response against SARS-CoV-2 even after a single dose

Direct Bypass Surgery Vs. Combined Bypass Surgery for Hemorrhagic Moyamoya Disease: A Comparison of Angiographic Outcomes

Objective: Extracranial-intracranial bypass is currently recognized as the optimal treatment for hemorrhagic-type moyamoya disease (MMD) which reduces incidence of rebleeding. Recent studies have reported the advantage of combined bypass over direct bypass for the general MMD patients. However, the effect of direct bypass and combined bypass surgery specifically for hemorrhagic-type MMD had not been investigated yet.Methods: Hemorrhagic-type MMD patients who underwent direct and combined bypass surgery with complete clinical and radiological documentation from a multicenter cohort between 2009 and 2017 were retrospectively included. Surgical methods included superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis (direct bypass), combined STA-MCA bypass with encephalodurosynangiosis (EDS), and combined STA-MCA bypass with encephaloduroarteriosynangiosis (EDAS). Matsushima standard on follow-up catheter angiography was used to assess surgical outcome. Modified Rankin Scale, incidence of rebleeding and ischemia during follow-up were recorded. Rebleeding-free survival rates between direct and combined bypass were compared by Kaplan-Meier analysis.Results: Sixty eight hemorrhagic-onset MMD patients were included in this study, among which 71 hemispheres were treated with surgery (direct bypass: 17; bypass+EDS: 24; bypass+EDAS: 30). Forty six (64.8%) hemispheres had satisfactory revascularization (Matsushima level 2–3) and 26 (36.6%) had poor neoangiogenesis. Matsushima level was not significantly different between surgical groups (P = 0.258). Good neoangiogenesis from dural grafts was achieved in 26 (36.6%) hemispheres, and good neoangiogenesis from STA grafts was only seen in 4 (out of 30, 12.5%) hemispheres. Multivariate analysis showed bypass patency [P < 0.001, OR (95%CI): 13.41 (3.28–54.80)] and dural neoangiogenesis [P < 0.001, OR (95%CI): 13.18 (3.26–53.36)] both independently contributed to good angiographic outcome. During follow-up, incidences of rebleeding or ischemic events, and re-bleeding free survival rate were not significantly different between surgical groups (P = 0.433, P = 0.559, and P = 0.997). However, patients who underwent combined bypass surgery had significantly lower mRS at follow-up comparing to patients who underwent direct bypass (P = 0.006).Conclusion: Combined bypass surgery and direct bypass surgery offered similar revascularization for hemorrhagic MMD. Bypass patency and dural angiogenesis both contributed to revascularization independently. The potential of indirect bypass to grow new vessels in hemorrhagic-MMD patients was generally limited, but dural leaflets offered better neoangiogenesis than STA grafts and was therefore recommended for surgical revascularization of hemorrhagic MMD

The Prevalence of Metabolically Healthy and Unhealthy Obesity according to Different Criteria

Objective: Obesity-related disease risks may vary depending on whether the subject has metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO). At least 5 definitions/criteria of obesity and metabolic disorders have been documented in the literature, yielding uncertainties in a reliable international comparison of obesity phenotype prevalence. This report aims to compare differences in MHO and MUO prevalence according to the 5 most frequently used definitions. Methods: A random sample of 4,757 adults aged 35 years and older (male 51.1%) was enrolled. Obesity was defined either according to body mass index or waist circumference, and the definitions of metabolic abnormalities were derived from 5 different criteria. Results: In MHO, the highest prevalence was obtained when using the homeostasis model assessment (HOMA) criteria (13.6%), followed by the Chinese Diabetes Society (11.4%), Adult Treatment Panel III (10.3%), Wildman (5.2%), and Karelis (4.2%) criteria; however, the MUO prevalence had an opposite trend to MHO prevalence. The magnitude of differences in the age-specific prevalence of MHO and MUO varied greatly and ranked in different orders. The proportion of insulin resistance for MHO and MUO individuals differed significantly regardless of which metabolic criterion was used. Conclusion: The prevalence of MHO and MUO in the Chinese population varies according to different definitions of obesity and metabolic disorders

Selection of Anti-Sulfadimidine Specific ScFvs from a Hybridoma Cell by Eukaryotic Ribosome Display

BACKGROUND:Ribosome display technology has provided an alternative platform technology for the development of novel low-cost antibody based on evaluating antibiotics derived residues in food matrixes. METHODOLOGY/PRINCIPAL FINDINGS:In our current studies, the single chain variable fragments (scFvs) were selected from hybridoma cell lines against sulfadimidine (SM(2)) by using a ribosome library technology. A DNA library of scFv antibody fragments was constructed for ribosome display, and then mRNA-ribosome-antibody (MRA) complexes were produced by a rabbit reticulocyte lysate system. The synthetic sulfadimidine-ovalbumin (SM(2)-OVA) was used as an antigen to pan MRA complexes and putative scFv-encoding genes were recovered by RT-PCR in situ following each panning. After four rounds of ribosome display, the expression vector pCANTAB5E containing the selected specific scFv DNA was constructed and transformed into Escherichia coli HB2151. Three positive clones (SAS14, SAS68 and SAS71) were screened from 100 clones and had higher antibody activity and specificity to SM(2) by indirect ELISA. The three specific soluble scFvs were identified to be the same molecular weight (approximately 30 kDa) by Western-blotting analysis using anti-E tag antibodies, but they had different amino acids sequence by sequence analysis. CONCLUSIONS/SIGNIFICANCE:The selection of anti-SM(2) specific scFv by in vitro ribosome display technology will have an important significance for the development of novel immunodetection strategies for residual veterinary drugs

A Fault Identification Method in Distillation Process Based on Dynamic Mechanism Analysis and Signed Directed Graph

Due to the complexity of materials and energy cycles, the distillation system has numerous working conditions difficult to troubleshoot in time. To address the problem, a novel DMA-SDG fault identification method that combines dynamic mechanism analysis based on process simulation and signed directed graph is proposed for the distillation process. Firstly, dynamic simulation is employed to build a mechanism model to provide the potential relationships between variables. Secondly, sensitivity analysis and dynamic mechanism analysis in process simulation are introduced to the SDG model to improve the completeness of this model based on expert knowledge. Finally, a quantitative analysis based on complex network theory is used to select the most important nodes in SDG model for identifying the severe malfunctions. The application of DMA-SDG method in a benzene-toluene-xylene (BTX) hydrogenation prefractionation system shows sound fault identification performance

Associations of blood pressure components with risks of cardiovascular events and all‐cause death in a Chinese population: A Prospective Study

Abstract The associations of blood pressure components with cardiovascular risks and death remain unclear, and the definition of wide pulse pressure (PP) is still controversial. Using data from 1257 participants without a history of cardiovascular disease, who were followed for 4.84 years, we performed multivariable Cox regression analyses to assess how systolic blood pressure (SBP), diastolic blood pressure (DBP), and PP contribute to risks of cardiovascular events and all‐cause death. Among all participants, SBP and PP were significantly associated with the risks of cardiovascular events and all‐cause death (all p < .05). DBP was not significantly associated with the risk of all‐cause death; rather, it was only associated with a marginally significant 1% increased risk for cardiovascular events (p = 0.051). In participants aged < 65 years, DBP was significantly associated with a 3% increased risk for cardiovascular events (hazard ratio [HR]: 1.03, 95% confidence interval [95% CI]: 1.01–1.06). The association between PP and cardiovascular events appeared to be J‐shaped in comparison to participants with the lowest‐risk PP (50–60 mmHg), with adjusted HRs of 1.71 (95% CI: 1.03–2.85), 1.63 (95% CI: 1.00–2.68), and 2.13 (95% CI: 1.32–3.43) in the <50, 60.0–72.5, and ≥72.5 mmHg subgroups, respectively. The optimal cutoff points of a wide PP for predicting the risks of cardiovascular events and all‐cause death were 70.25 and 76.25 mmHg, respectively. SBP and PP had a greater effect on cardiovascular risk, whereas DBP independently influenced cardiovascular events in middle‐aged participants. Considerable PP alterations should be avoided in antihypertensive treatment

Role of Cue Training, Context, and Stimulus Intensity on Fear Generalization in Humans

Fear generalization is a crucial mechanism underlying maladaptive behavior, but factors influencing this process are not fully understood. We investigated the effects of cue training and context on fear generalization and how cognitive rules influence responses to different conditions. We also examined the role of stimulus intensity in fear generalization to provide insight into fear generalization mechanisms. Participants (n = 104) completed a fear emotion task with two stages: acquisition and generalization testing. Subjective fear expectancy ratings were used as outcome measures. Participants who received single threat cue training exhibited stronger fear generalization responses than those who received discrimination training with threat and safe cues. Participants who received discrimination training and used linear rules had the strongest fear response to the largest stimulus. Therefore, a safe cue may mitigate fear generalization but could increase fear responses to more intense stimuli. Altering context did not change the fear generalization response because fear generalization is mainly governed by the association between the conditioned stimulus and the unconditioned fear stimulus. The present study emphasizes the multifaceted nature of fear generalization and the importance of examining multiple factors to understand this phenomenon. These findings elucidate fear learning and provide insights needed for effective interventions for maladaptive behavior