Immunogenicity of mRNA vs. BBV152 vaccine boosters against Omicron subvariants: Final results from Phase B of the PRIBIVAC study, a randomized clinical trial.

BACKGROUND: BBV152 (Covaxin™) is a whole-virion inactivated SARS-CoV-2 vaccine mixed with an immune adjuvant. We aimed to compare immune responses after booster vaccination with heterologous BBV152 versus homologous mRNA vaccine. METHODS: We conducted a randomized, participant-blinded, controlled trial. Fifty mRNA-vaccinated participants were enrolled and randomized to receive an mRNA booster (n = 26) or BBV152 (n = 24). Blood samples were collected pre-vaccination, and at Day 7, 28, 180 and 360 post-booster for analysis of humoral and cellular immune responses. Primary end point was the SARS-CoV-2 anti-spike antibody titer at day 28. RESULTS: Recruitment began in January 2022 and was terminated early due to the BBV152 group meeting pre-specified criteria for futility. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBV152 (2004 IU/mL; 95 % confidence interval [CI], 1132-3548) vs mRNA (26,669 IU/mL; 95 % CI, 21,330-33,266; p < 0.0001), but comparable levels of spike-specific CD4 and cytotoxic T-cells were observed. Anti-spike antibody titers remained significantly different at Day 180: BBV152 4467 IU/mL (95 % CI, 1959-10,186) vs mRNA 20,749 IU/mL (95 % CI, 12,303-35,075; p = 0.0017). Levels of surrogate virus neutralizing antibodies against ancestral and Omicron subvariants BA.1 and BA.2 were significantly higher among mRNA recipients at Day 180, including after adjusting for intercurrent infection. By Day 360, anti-spike antibody titers and neutralizing antibody levels against Omicron subvariants became similar between vaccine groups. By the end of the study, 16 in each arm (mRNA 64 % and BBV152 69.6 %) had breakthrough infections and time to COVID-19 infection between vaccine groups were similar (p = 0.63). CONCLUSIONS: Wild-type SARS-CoV-2 anti-spike antibody titer and surrogate virus neutralizing test levels against wild-type SARS-CoV-2 and Omicron subvariants BA.1/BA.2/BA.5 were significantly higher at Day 28 and 180 in individuals who received booster vaccination with an mRNA vaccine compared with BBV152. CLINICAL TRIAL REGISTRATION NUMBER: NCT05142319.

[Effect of compatibility of Corni Fructus before and after wine-processing with Astragali Radix on plasma metabolomics in diabetic nephropathy rats based on UHPLC-Q-TOF-MS/MS].

Based on the processing and compatibility, this study explored the effects of components in Corni Fructus(CF) and Astragali Radix(AR) on plasma metabolomics in diabetic nephropathy rats. SD rats were randomly divided into four groups and diabetic nephropathy rat model was induced by high-fat diet combined with 30 mg·kg~(-1) streptozotocin(STZ). Histopathological observations of kidney tissue sections of rats in each group were conducted using HE, PAS, and Masson staining. Ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS/MS) metabolomics method was employed to investigate the effects of CF before and after wine-processing combined with AR-related components on plasma metabolites in diabetic nephropathy rats. After drug treatment, kidney tissue damage and interstitial collagen fiber deposition area in diabetic nephropathy rats were improved to varying degrees(P<0.001). The detection results of plasma metabolomics showed that 71 biomarkers related to the pathogenesis of diabetic nephropathy were identified in diseased rats, mainly involving linoleic acid metabolism, caffeine metabolism, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arachidonic acid metabolism, phenylalanine metabolism, retinol metabolism, and ether lipid metabolism. After drug intervention, 26 of them were significantly downregulated, with better efficacy observed in precision processed herb-pair group(P-CG_5). This study elucidated from the perspective of plasma metabolomics that P-CG_5 could improve metabolic disorders in diabetic nephropathy through pathways such as phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and caffeine metabolism, providing theoretical support and experimental basis for the clinical application of CF and AR compatibility in traditional Chinese medicine.

Sensitive fluorescence detection of miRNA-124 in cardiomyocytes under oxidative stress using a nucleic acid probe.

MicroRNAs (miRNAs) are small noncoding RNAs of 18-25 bases. miRNAs are also important new biomarkers that can be used for disease diagnosis in the future. Studies have shown that miR-124 levels are significantly elevated during acute myocardial infarction (AMI) and play a key role in the cardiovascular system. A variety of methods have been established to detect myocardial infarction-related miRNAs. However, most require complex miRNA extraction and isolation, and these methods are virtually undetectable when RNA levels are low in the sample. It may lead to biased results. Thus, it is necessary to develop a technique that can detect miRNA without extracting it, which means that intracellular detection is of great significance. Here, we improved the traditional silicon spheres and obtained a biosensor that could effectively capture and detect specific noncoding nucleic acids through the layer-by-layer assembly method. The sensor is protected by hyaluronic acid so it can successfully escape the lysosome into the cell and achieve detection. With the help of a full-featured microplate reader, we determined that the detection limit of the biosensor could reach 1 fM, meeting the needs of intracellular detection. At the same time, we prepared an oxidative stress cardiomyocyte infarction model and successfully captured the overexpressed miR-124 in the infarcted cells to achieve in situ detection. This study could provide a new potential tool to develop miRNAs for sensitive diagnosis in AMI, and the proposed strategy implies its potential for biomedical research.

Causal Relationships Between Circulating Inflammatory Proteins and Obstructive Sleep Apnea: A Bidirectional Mendelian Randomization Study.

Purpose: Clinical studies have demonstrated the intricate association between the onset and progression of obstructive sleep apnea (OSA) and the activation of the inflammatory cascade reaction. This study delves into investigating the causal links between 91 circulating inflammatory proteins (CIPs) and OSA through the application of Mendelian randomization (MR) techniques. Methods: Utilizing genetic data on OSA sourced from the Finnish Biobank (FinnGen) Genome-wide Association Studies (GWAS) of the European population, alongside summary-level GWAS data of CIPs from 14,824 European participants, we conducted a bidirectional MR study. Results: This study suggests that several factors may be associated with the risk of OSA. IL-17C (odds ratio (OR) = 1.090, p = 0.0311), CCL25 (OR = 1.079, p = 0.0493), FGF-5 (OR = 1.090, p = 0.0003), CD5 (OR = 1.055, p = 0.0477), and TNFSF14 (OR = 1.092, p = 0.0008) may positively correlate with OSA risk. Conversely, IL-20RA (OR = 0.877, p = 0.0107), CCL19 (OR = 0.933, p = 0.0237), MIP-1 alpha (OR = 0.906, p = 0.0042), Flt3L (OR = 0.941, p = 0.0019), CST5 (OR = 0.957, p = 0.0320), OPG (OR = 0.850, p = 0.0001), and TRAIL (OR = 0.956, p = 0.0063) may reduce the risk of OSA. Additionally, elevated levels of IL-10RA (OR = 1.153, p = 0.0478) were observed as a consequence of OSA. Conversely, OSA may potentially lead to decreased levels of CCL28 (OR = 0.875, p = 0.0317), DNER (OR = 0.874, p = 0.0324), FGF-21 (OR = 0.846, p = 0.0344), and CSF-1 (OR = 0.842, p = 0.0396). Conclusion: Through this bidirectional MR study, we have identified 12 upstream regulatory proteins and 5 downstream effect proteins that are linked to OSA. These findings hold promise in providing potential therapeutic targets for the inflammatory mechanisms underlying OSA.

Imprinting of IgA responses in previously infected individuals receiving bivalent mRNA vaccines (WT and BA.4/BA.5 or WT and BA.1).

OBJECTIVES: The emergence of new SARS-CoV-2 variants has led to the development of Omicron-targeting bivalent mRNA vaccines. It is crucial to understand how bivalent vaccines may improve antibody responses against new variants. METHODS: A total of 107 participants, who had three COVID-19 WT mRNA vaccine doses, were recruited, and given either a monovalent (WT) or a bivalent mRNA vaccination (Pfizer/BioNTech Bivalent (WT and BA.4/BA.5) or Moderna Bivalent (WT and BA.1). Blood samples were taken before booster and at 28 days post-booster. RESULTS: We found significantly lower fold change in serum binding IgA responses against BA.1, BA.5 and EG.5.1 spike in the bivalent booster group, compared with the monovalent (WT) booster group, following vaccination. However, this was only observed in individuals with prior infection. The relative fold change in serum binding IgA response was more skewed towards WT over variant (BA.1, BA.5 or EG.5.1) spike in previously infected bivalent-booster-vaccinees, as compared with previously infected monovalent-(WT)-booster-vaccinees. CONCLUSION: The findings suggest imprinting of antibody responses that is shaped by the first vaccination (WT spike). Previous infection also affects the boosting effect of follow-up vaccination. Studies are needed to understand how to induce a robust and long-lasting IgA immunity for protection against COVID-19 infection.

Treatment and nursing care of a patient diagnosed with malignant hyperthermia after general anesthesia: a case report.

Malignant hyperthermia (MH), characterized by severe myoclonus, pyrexia, tachycardia, hypertension, elevated muscle enzymes, and hypercapnia, often occurs in patients with congenital deformities or genetic disorders. Although the reported incidence rate is as low as 1:5000 to 1:100,000, patients with MH exhibit rapid aggravation and an elevated mortality rate. Thus, MH is associated with substantial perioperative risk. Successful treatment of patients with MH largely depends on early diagnosis and timely effective treatment. This clinical report provides a detailed description of a patient with newly diagnosed MH who developed a rapid rise in body temperature, end-tidal carbon dioxide, and heart rate during maxillary osteotomy. After successful rescue, the patient recovered smoothly during the postoperative period, indicating the importance of intraoperative monitoring, early diagnosis, effective treatment, and postoperative monitoring. This case is expected to serve as a reference for future interventions and healthcare practices in managing other patients with MH.

[Characterization of carbon and oxygen isotopes of plant on climate and plant physiology at the southeastern margin of Qinghai-Tibet Plateau, China]. / é’è—é«˜åŽŸä¸œå—ç¼˜æ¤ç‰©ç¢³æ°§åŒä½ç´ å¯¹æ°”å€™åŠæ¤ç‰©ç”Ÿç†çš„è¡¨å¾.

To investigate the correlation between carbon and oxygen isotope compositions of plant cellulose and climatic factors as well as plant physiological indices on the southeastern margin of the Qinghai-Tibet Plateau, we examined plant species in eight sampling sites with similar latitudes and different longitudes in this region. Through the characteristics of δ13C and δ18O values, fractionation values (Δ13C and Δ18O) in leaf cellulose, we discussed water use efficiency (WUE) and the environmental factors, the variation of carbon and oxygen isotopes in the southeastern margin of the Qinghai-Tibet Plateau with elevation and longitude, and revealed the indication degrees of isotopic signals to different environments and vegetation physiology. By using the semi-quantitative model of carbon and oxygen dual isotopes, we investigated the physiological adaptation mechanisms of plants to varying environmental conditions. The results demonstrated that both Δ13C and Δ18O of cellulose decreased with increasing elevation and longitude, and Δ13C was more influenced by longitude, while Δ18O was more susceptible to elevation variation. Additionally, Δ13C and Δ18O were significantly and positively correlated with temperature (TEM), precipitation (PRE), potential evapotranspiration (PET), and relative humidity (RH). PRE was the dominant meteorological factor driving the variation of Δ13C, while RH was the dominant meteorological factor influencing Δ18O variation. In contrast to Δ13C, WUE showed a stronger correlation with elevation than with longitude, which increased as elevation and longitude increased. According to the carbon-oxygen model, plant stomatal conductance (gs) and photosynthetic capacity (Amax) decreased with increasing precipitation and relative humidity, while the values increased with increasing elevation and longitude. The combined analysis of carbon and oxygen isotopes of organic matters would yield additional environmental and gas exchange information for studies on climate tracing and vegetation physiology studies on the southeastern margin of the Qinghai-Tibet Plateau.

Clonal integration of stress signal induces morphological and physiological response of root within clonal network.

Clonal integration of defense or stress signal induced systemic resistance in leaf of interconnected ramets. However, similar effects of stress signal in root are poorly understood within clonal network. Clonal fragments of Centella asiaticas with first-young, second-mature, third-old and fourth-oldest ramets were used to investigate transportation or sharing of stress signal among interconnected ramets suffering from low water availability. Compared with control, oxidative stress in root of the first-young, second-mature and third-old ramets was significantly alleviated by exogenous ABA application to the fourth-oldest ramets as well as enhancement of antioxidant enzyme (SOD, POD, CAT and APX) activities and osmoregulation ability. Surface area and volume in root of the first-young ramets were significantly increased and total length in root of the third-old ramets was significantly decreased. POD activity in root of the fourth-oldest and third-old ramets was significantly enhanced by exogenous ABA application to the first-young ramets. Meanwhile, total length and surface area in root of the fourth-oldest and third-old ramets were significantly decreased. Ratio of belowground to aboveground biomass in the whole clonal fragments was significantly increased by exogenous ABA application to the fourth-oldest or first-young ramets. It is suggested that transportation or sharing of stress signal may induce systemic resistance in root of interconnected ramets. Specially, transportation or sharing of stress signal against phloem flow was observed in the experiment. Possible explanation is that rapid recovery of foliar photosynthesis in first-young ramets subjected to exogenous ABA application can partially reverse phloem flow within clonal network. Thus, our experiment provides insight into ecological implication on clonal integration of stress signal.

Systematic sequential therapy for ex vivo liver resection and autotransplantation: A case report and review of literature.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) is a highly malignant tumor arising from the biliary tree. Radical surgery is the only treatment offering a chance of long-term survival. However, limited by the tumor's anatomic location and peri-vascular invasion, most patients lose the chance for curative treatment. Therefore, more methods to increase the resectability of tumors as well as to improve outcomes are needed. CASE SUMMARY: A 68-year-old female patient had a hepatic hilar mass without obvious symptoms. Laboratory results showed hepatitis B positivity. Magnetic resonance imaging indicated that the mass (maximum diameter: 41 mm) invaded the left and right branches of the main portal vein, as well as the middle, left and right hepatic veins; enlarged lymph nodes were also detected in the hilum. The patient was diagnosed with pCCA, and the clinical stage was determined to be T4N1M0 (stage IIIC). Considering the tumor's anatomic location and vascular invasion, systematic conversion therapy followed by ex vivo liver resection and autotransplantation (ELRA) was determined as personalized treatment for this patient. Our original systemic sequential therapeutic strategy (lenvatinib and tislelizumab in combination with gemcitabine and cisplatin) was successfully adopted as conversion therapy because she achieved partial response after three cycles of treatment, without severe toxicity. ELRA, anastomotic reconstruction of the middle hepatic vein, right hepatic vein, root of portal vein, inferior vena cava and right hepatic artery, and lymph node dissection were performed at one month after systemic therapy. Pathological and immunohistochemical examination confirmed the diagnosis of pCCA with lymph node metastasis. Although the middle hepatic vein was partially obstructed four months later, hepatic vein stent implantation successfully addressed this problem. The patient has survived for 22 mo after the diagnosis, with no evidence of recurrence or metastasis. CONCLUSION: An effective therapeutic strategy for conversion therapy greatly increases the feasibility and efficiency of ELRA.

Higher Delta variant-specific neutralizing antibodies prevented infection in close contacts vaccinated with ancestral mRNA vaccines during the SARS-CoV-2 Delta wave.

Identification of the risk factors and the high-risk groups which are most vulnerable is critical in COVID-19 disease management at a population level. Evaluating the efficacy of vaccination against infections is necessary to determine booster vaccination strategies for better protection in high-risk groups. In this study, we recruited 158 mRNA-vaccinated individuals during the Delta wave of SARS-CoV-2 infections in Singapore and examined the antibody profiles of infected individuals. We found that, despite high exposure due to communal living conditions in proximity, 4% of individuals (6/158) had PCR-confirmed infections and 96% (152/158) remained uninfected. Time-course analysis of the antibody profile at the start and the end of quarantine period showed Delta-specific boosting of anti-spike antibody response in 57% of the uninfected individuals (86/152). In the remaining 43% of the uninfected individuals (66/152) with no Delta-specific antibody boost, we found a higher Delta-specific antibody response at the start of quarantine period, which correlated with higher Delta pseudovirus neutralizing capacity. Our findings indicate that a higher basal variant-specific antibody response in the mRNA-vaccinated individuals contributes to better protection against infections by the new emerging SARS-CoV-2 variants.

Variant-specific IgA protects against Omicron infection.

BACKGROUND: The emergence of rapidly evolving SARS-CoV-2 variants, coupled with waning vaccine-induced immunity, has contributed to the rise of vaccine breakthrough infections. It is crucial to understand how vaccine-induced protection is mediated. METHODS: We examined two prospective cohorts of mRNA-vaccinated-and-boosted individuals during the Omicron wave of infection in Singapore. RESULTS: We found that, individuals, who remain uninfected over the follow-up period, had a higher variant-specific IgA, but not IgG, antibody response at 1-month post booster vaccination, compared with individuals who became infected. CONCLUSIONS: We conclude that IgA may have a potential contributory role in protection against Omicron infection.

Integrative analysis of DNA methylome and transcriptome reveals epigenetic regulation of bisphenols-induced cardiomyocyte hypertrophy.

Cardiac hypertrophy, a kind of cardiomyopathic abnormality, might trigger heart contractile and diastolic dysfunction, and even heart failure. Currently, bisphenols (BPs) including bisphenol A (BPA), and its alternatives bisphenol AF (BPAF), bisphenol F (BPF) and bisphenol S (BPS) are ubiquitously applied in various products and potentially possess high cardiovascular risks for humans. However, the substantial experimental evidences of BPs on heart function, and their structure-related effects on cardiomyocyte hypertrophy are still urgently needed. DNA methylation, a typical epigenetics, play key roles in BPs-induced transcription dysregulation, thereby affecting human health including cardiovascular system. Thus, in this study, we performed RNA-seq and reduced representation bisulfite sequencing (RRBS) to profile the landscapes of BPs-induced cardiotoxicity and to determine the key roles of DNA methylation in the transcription. Further, the capabilities of three BPA analogues, together with BPA, in impacting heart function and changing DNA methylation and transcription were compared. We concluded that similar to BPA, BPAF, BPF and BPS exposure deteriorated heart function in a mouse model, and induced cardiomyocyte hypertrophy in a H9c2 cell line. BPAF, BPF and BPS all played BPA-like roles in both transcriptive and methylated hierarchies. Moreover, we validated the expression levels of four cardiomyocyte hypertrophy related candidate genes, Psmc1, Piptnm2, Maz and Dusp18, which were all upregulated and with DNA hypomethylation. The findings on the induction of BPA analogues on cardiomyocyte hypertrophy and DNA methylation revealed their potential detrimental risks in heart function of humans.

Third dose of BNT162b2 improves immune response in liver transplant recipients to ancestral strain but not Omicron BA.1 and XBB.

Vaccine immunogenicity in transplant recipients can be impacted by the immunosuppressive (IS) regimens they receive. While BNT162b2 vaccination has been shown to induce an immune response in liver transplant recipients (LTRs), it remains unclear how different IS regimens may affect vaccine immunogenicity after a third BNT162b2 dose in LTRs, which is especially important given the emergence of the Omicron sublineages of SARS-CoV-2. A total of 95 LTRs receiving single and multiple IS regimens were recruited and offered three doses of BNT162b2 during the study period. Blood samples were collected on days 0, 90, and 180 after the first BNT162b2 dose. At each time point, levels of anti-spike antibodies, their neutralizing activity, and specific memory B and T cell responses were assessed. LTRs receiving single IS regimens showed an absence of poor immunogenicity, while LTRs receiving multiple IS regimens showed lower levels of spike-specific antibodies and immunological memory compared to vaccinated healthy controls after two doses of BNT162b2. With a third dose of BNT162b2, spike-specific humoral, memory B, and T cell responses in LTR significantly improved against the ancestral strain of SARS-CoV-2 and were comparable to those seen in healthy controls who received only two doses of BNT162b2. However, LTRs receiving multiple IS regimens still showed poor antibody responses against Omicron sublineages BA.1 and XBB. A third dose of BNT162b2 may be beneficial in boosting antibody, memory B, and T cell responses in LTRs receiving multiple IS regimens, especially against the ancestral Wuhan strain of SARS-CoV-2. However, due to the continued vulnerability of LTRs to presently circulating Omicron variants, antiviral treatments such as medications need to be considered to prevent severe COVID-19 in these individuals.

Discrimination of Liver Metastases of Digestive System Neuroendocrine Tumors From Neuroendocrine Carcinoma by Computed Tomography-Based Radiomics Analysis.

OBJECTIVE: The aim of the study is to investigate the value of computed tomography (CT) radiomics features to discriminate the liver metastases (LMs) of digestive system neuroendocrine tumors (NETs) from neuroendocrine carcinoma (NECs). METHODS: Ninety-nine patients with LMs of digestive system neuroendocrine neoplasms from 2 institutions were included. Radiomics features were extracted from the portal venous phase CT images by the Pyradiomics and then selected by using the t test, Pearson correlation analysis, and least absolute shrinkage and selection operator method. The radiomics score (Rad score) for each patient was constructed by linear combination of the selected radiomics features. The radiological model was constructed by radiological features using the multivariable logistic regression. Then, the combined model was constructed by combining Rad score and the radiological model into logistic regression. The performance of all models was evaluated by the receiver operating characteristic curves with the area under curve (AUC). RESULTS: In the radiological model, only the enhancement degree (odds ratio, 8.299; 95% confidence interval, 2.070-32.703; P = 0.003) was an independent predictor for discriminating the LMs of digestive system NETs from those of NECs. The combined model constructed by the Rad score in combination with the enhancement degree showed good discrimination performance, with AUCs of 0.893, 0.841, and 0.740 in the training, testing, and external validation groups, respectively. In addition, it performed better than radiological model in the training and testing groups (AUC, 0.893 vs 0.726; AUC, 0.841 vs 0.621). CONCLUSIONS: The CT radiomics might be useful for discrimination LMs of digestive system NECs from NETs.

NUCKS1 promotes the progression of colorectal cancer via activating PI3K/AKT/mTOR signaling pathway.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) is highly expressed in a variety of malignant tumors and functions as an oncogene; however, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the function and regulatory mechanisms of NUCKS1 and potential therapeutic agents targeting NUCKS1 in CRC. We knocked down and overexpressed NUCKS1 in CRC cells and explored its effects in vitro and in vivo. Flow cytometry, CCK-8, Western blotting, colony formation, immunohistochemistry, in vivo tumorigenic, and transmission electron microscopy analyses were performed to determine the effects of NUCKS1 on CRC cell function. LY294002 was used to examine the mechanism of NUCKS1 expression in CRC cells. Potential therapeutic agents for NUCKS1-high CRC patients were analyzed using the CTRP and PRISM datasets, and the function of selected agents was determined by CCK-8 and Western blotting. We revealed that NUCKS1 was highly expressed in CRC tissues and clinically correlated with poor prognosis in CRC patients. NUCKS1 knockdown induces cell cycle arrest, inhibits CRC cell proliferation, and promotes apoptosis and autophagy. These results were reversed when NUCKS1 was overexpressed. Mechanistically, NUCKS1 exerts a cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway. This was reversed when LY294002 was used to inhibit the PI3K/AKT pathway. Furthermore, we determined that mitoxantrone exhibited high drug sensitivity in NUCKS1-overexpressing CRC cells. This work demonstrated NUCKS1 plays a crucial role in CRC progression via the PI3K/AKT/mTOR signaling pathway. Additionally, mitoxantrone may be a potential therapeutic agent for CRC treatment. Therefore, NUCKS1 represents a promising anti-tumor therapeutic target.

Efficient recall of SARS-CoV-2 variant-reactive B cells and T responses in the elderly upon heterologous mRNA vaccines as boosters.

Waning antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of variants of concern highlight the need for booster vaccinations. This is particularly important for the elderly population, who are at a higher risk of developing severe coronavirus disease 2019 (COVID-19) disease. While studies have shown increased antibody responses following booster vaccination, understanding the changes in T and B cell compartments induced by a third vaccine dose remains limited. We analyzed the humoral and cellular responses in subjects who received either a homologous messenger RNA(mRNA) booster vaccine (BNT162b2 + BNT162b2 + BNT162b2; ''BBB") or a heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; ''BBM") at Day 0 (prebooster), Day 7, and Day 28 (postbooster). Compared with BBB, elderly individuals (≥60 years old) who received the BBM vaccination regimen display higher levels of neutralizing antibodies against the Wuhan and Delta strains along with a higher boost in immunoglobulin G memory B cells, particularly against the Omicron variant. Circulating T helper type 1(Th1), Th2, Th17, and T follicular helper responses were also increased in elderly individuals given the BBM regimen. While mRNA vaccines increase antibody, T cell, and B cell responses against SARS-CoV-2 1 month after receiving the third dose booster, the efficacy of the booster vaccine strategies may vary depending on age group and regimen combination.

One-Pot Facile Encapsulation of Dimethyloxallyl Glycine by Nanoscale Zeolitic Imidazolate Frameworks-8 for Enhancing Vascularized Bone Regeneration.

In the process of bone tissue regeneration, regulation of osteogenesis-angiogenesis coupling is of great importance. Therefore, dimethyloxallyl glycine (DMOG) is loaded by nanoscale zeolitic imidazolate frameworks-8 (ZIF-8) to obtain a drug-loading system that can promote osteogenesis-angiogenesis coupling. Characterization of the drug-loading nanoparticles (DMOG@ZIF-8) reveals that DMOG is successfully loaded into ZIF-8 by two different methods, and the DMOG@ZIF-8 is prepared using the one-pot method (OD@ZIF-8) achieves higher loading efficiency and longer release time than those prepared using the post-loading method (PD@ZIF-8). In vitro studies found that DMOG@ZIF-8 significantly enhances the migration, tube formation, and angiogenesis-related protein secretion of human umbilical vein endothelial cells as well as the extracellular matrix mineralization, alkaline phosphatase activity, and osteogenesis-related protein secretion of bone marrow mesenchymal stem cells. Moreover, OD@ZIF-8 nanoparticles are more efficient than PD@ZIF-8 nanoparticles in induction of osteogenesis-angiogenesis coupling. Then, in vivo cranial critical defect model shows that the addition of OD@ZIF-8 significantly promotes vascularized bone formation as indicated by the results including microcomputed tomographic, histological and immunofluorescence staining, and so on. Taken together, loading ZIF-8 with DMOG may be a promising solution for critical-sized bone defect reconstruction and the one-pot method is preferred in the preparation of such drug-loading system.

Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections.

Introduction: COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods: Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results: We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion: While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.