With the continuous emergence of new SARS-CoV-2 variants that feature increased transmission and immune escape, there is an urgent demand for a better vaccine design that will provide broader ...neutralizing efficacy.
We report an mRNA-based vaccine using an engineered "hybrid" receptor binding domain (RBD) that contains all 16 point-mutations shown in the currently prevailing Omicron and Delta variants.
A booster dose of hybrid vaccine in mice previously immunized with wild-type RBD vaccine induced high titers of broadly neutralizing antibodies against all tested SARS-CoV-2 variants of concern (VOCs). In naïve mice, hybrid vaccine generated strong Omicron-specific neutralizing antibodies as well as low but significant titers against other VOCs. Hybrid vaccine also elicited CD8+/IFN-γ+ T cell responses against a conserved T cell epitope present in wild type and all VOCs.
These results demonstrate that inclusion of different antigenic mutations from various SARS-CoV-2 variants is a feasible approach to develop cross-protective vaccines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Metastasis is responsible for most cancer mortality, but its molecular mechanism has not been completely understood. In addition to coding genes and miRNAs, the contribution of long noncoding RNAs ...(lncRNAs) to tumor metastatic dissemination and the mechanisms controlling their expression are areas of intensive investigation. Here, we show that lncRNA NORAD is downregulated in lung and breast cancers, and that NORAD low expression in these cancer types is associated with lymph node metastasis and poor prognosis. NORAD is transcriptionally repressed by the Hippo pathway transducer YAP/TAZ-TEAD complex in conjunction with the action of NuRD complex. Functionally, NORAD elicits potent inhibitory effects on migration and invasion of multiple lung and breast cancer cell lines, and repression of NORAD expression participates in the migration- and invasion-stimulatory effects of the YAP pathway. Mechanistically, NORAD exploits its multiple repeated sequences to function as a multivalent platform for binding and sequestering S100P, thereby suppressing S100P-elicited pro-metastatic signaling network. Using cell and mouse models, we show that the S100P decoy function of NORAD suppresses lung and breast cancer migration, invasion, and metastasis. Together, our study identifies NORAD as a novel metastasis suppressor, elucidates its regulatory and functional mechanisms, and highlights its prognostic value.
Conjugated polymers (CPs) have recently gained increasing attention as photocatalysts for sunlight-driven hydrogen evolution. However, they suffer from insufficient electron output sites and poor ...solubility in organic solvents, severely limiting their photocatalytic performance and applicability. Herein, solution-processable all-acceptor (A
-A
)-type CPs based on sulfide-oxidized ladder-type heteroarene are synthesized. A
-A
-type CPs showed upsurging efficiency improvements by two to three orders of magnitude, compared to their donor-acceptor -type CP counterparts. Furthermore, by seawater splitting, PBDTTTSOS exhibited an apparent quantum yield of 18.9% to 14.8% at 500 to 550 nm. More importantly, PBDTTTSOS achieved an excellent hydrogen evolution rate of 35.7 mmol h
g
and 150.7 mmol h
m
in the thin-film state, which is among the highest efficiencies in thin film polymer photocatalysts to date. This work provides a novel strategy for designing polymer photocatalysts with high efficiency and broad applicability.
COVID-19 in humans is caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that belongs to the beta family of coronaviruses. SARS-CoV-2 causes severe respiratory illness in 10-15% ...of infected individuals and mortality in 2-3%. Vaccines are urgently needed to prevent infection and to contain viral spread. Although several mRNA- and adenovirus-based vaccines are highly effective, their dependence on the "cold chain" transportation makes global vaccination a difficult task. In this context, a stable lyophilized vaccine may present certain advantages. Accordingly, establishing additional vaccine platforms remains vital to tackle SARS-CoV-2 and any future variants that may arise. Vaccinia virus (VACV) has been used to eradicate smallpox disease, and several attenuated viral strains with enhanced safety for human applications have been developed. We have generated two candidate SARS-CoV-2 vaccines based on two vaccinia viral strains, MVA and v-NY, that express full-length SARS-CoV-2 spike protein. Whereas MVA is growth-restricted in mammalian cells, the v-NY strain is replication-competent. We demonstrate that both candidate recombinant vaccines induce high titers of neutralizing antibodies in C57BL/6 mice vaccinated according to prime-boost regimens. Furthermore, our vaccination regimens generated TH1-biased immune responses in mice. Most importantly, prime-boost vaccination of a Syrian hamster infection model with MVA-S and v-NY-S protected the hamsters against SARS-CoV-2 infection, supporting that these two vaccines are promising candidates for future development. Finally, our vaccination regimens generated neutralizing antibodies that partially cross-neutralized SARS-CoV-2 variants of concern.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit ...vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 μg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 μg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 μg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.
Abstract
Background
Increasing evidences have suggested an important role of microRNAs (miRNAs) in regulating cell death processes including NETosis and apoptosis. Dysregulated expression of miRNAs ...and increased formation of neutrophil extracellular traps (NETs) and apoptosis participate in autoimmune-mediated diffuse alveolar hemorrhage (DAH), mostly associated with pulmonary capillaritis in systemic lupus erythematosus (SLE) patients. In particular, besides the inhibition of apoptosis, miR-146a can control innate and acquired immune responses, and regulate the toll-like receptor pathway through targeting TRAF6 to reduce the expression of pro-inflammatory cytokines/chemokines like IL-8, a NETosis inducer.
Methods
Expression of miR-146a, TRAF6 and NETs were examined in peripheral blood neutrophils (PBNs) and lung tissues from SLE-associated DAH patients, and in neutrophils and pristane-induced DAH lung tissues from C57BL/6 mice. To assess NETs formation, we examined NETosis-related DNAs morphology and crucial mediators including protein arginine deiminase 4 and citrullinated Histone 3. Expression of miR-146a and its endogenous RNA SNHG16 were studied in HL-60 promyelocytic cells and MLE-12 alveolar cells during NETosis and apoptosis processes, respectively. MiR-146a-overexpressed and CRISPR-Cas13d-mediated SNHG16-silenced HL-60 cells were investigated for NETosis. MiR-146a-overexpressed MLE-12 cells were analyzed for apoptosis. Pristane-injected mice received intra-pulmonary miR-146a delivery to evaluate therapeutic efficacy in DAH.
Results
In DAH patients, there were down-regulated miR-146a levels with increased TRAF6 expression and PMA/LPS-induced NETosis in PBNs, and down-regulated miR-146a levels with increased TRAF6, high-mobility group box 1 (HMGB1), IL-8, NETs and apoptosis expression in lung tissues. HMGB1-stimulated mouse neutrophils had down-regulated miR-146a levels with increased TRAF6, IL-8 and NETs expression. PMA-stimulated HL-60 cells had down-regulated miR-146a levels with enhanced NETosis. MiR-146a-overexpressed or SNHG16-silenced HL-60 cells showed reduced NETosis. Apoptotic MLE-12 cells had down-regulated miR-146a expression and increased HMGB1 release, while miR-146a-overexpressed MLE-12 cells showed reduced apoptosis and HMGB1 production. There were down-regulated miR-146a levels with increased TRAF6, HMGB1, IL-8, NETs and apoptosis expression in mouse DAH lung tissues. Intra-pulmonary miR-146a delivery could suppress DAH by reducing TRAF6, IL-8, NETs and apoptosis expression.
Conclusions
Our results demonstrate firstly down-regulated pulmonary miR-146a levels with increased TRAF6 and IL-8 expression and NETs and apoptosis formation in autoimmune-mediated DAH, and implicate a therapeutic potential of intra-pulmonary miR-146a delivery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
The increased expression of programmed death‐ligands 1 and 2 (PD‐L1 and PD‐L2, respectively) on tumour cells contributes to immune evasion, suggesting that these proteins are attractive ...therapeutic targets. This study aimed to evaluate the validity of cerebrospinal fluid (CSF) soluble PD‐L1 (sPD‐L1) and soluble PD‐L2 (sPD‐L2) as biomarkers for primary central nervous system lymphoma (PCNSL). We determined the CSF concentrations of sPD‐L1 and sPD‐L2 in 46 patients with PCNSL using enzyme‐linked immunosorbent assays (ELISAs). A control group comprised 153 patients with other brain tumours, inflammatory/infectious status, or neurodegenerative diseases. Only CSF sPD‐L1 levels were significantly higher in patients with PCNSL relative to the controls. CSF sPD‐L1 also exhibited superior overall discrimination performance compared to CSF sPD‐L2 in diagnosing PCNSL. Compared with patients with PCNSL with low CSF sPD‐L1 levels, more patients with high levels had high serum lactate dehydrogenase levels, leptomeningeal involvement, and deep‐brain involvement. Furthermore, CSF sPD‐L1 could predict poor survival in PCNSL but CSF sPD‐L2 could not. Intriguingly, CSF sPD‐L1 levels were correlated with disease status and their dynamic changes post treatment could predict time to relapse. In conclusion, this study identified CSF sPD‐L1 as a promising prognostic biomarker, indicating a therapeutic potential of PD‐L1 blockade in PCNSL.
This study investigates the cross‐linguistic transfer of literacy skills in Spanish–English, Chinese–English bilingual, and English monolingual children (N = 283, 5–10 years). Research question 1 ...examines English literacy and asks how phonological and morpho‐semantic skills contribute to word reading as a function of children's language background. Structural equation modeling revealed contrasting bilingual effects: compared to English monolinguals, Spanish–English bilinguals relied more on phonological awareness in word reading, whereas Chinese–English bilinguals relied more on lexical knowledge. Research question 2 examines relations between bilinguals’ heritage language proficiency and English literacy. Results revealed direct and indirect effects of heritage language meta‐linguistic skills on English word reading. The study yields implications for reading theories and instructional practices in optimizing literacy in linguistically diverse children.
Although prior research into the relationship between volume and outcome indicates that this relationship is not linear and that an optimal volume should be specified, consensus is lacking regarding ...the ideal value of this optimal volume. The purposes of this study were to use a visual method to identify surgeon- and hospital-volume thresholds and to examine the relationships of surgeon and hospital volume thresholds to 30-day readmission.
A retrospective nationwide population-based study design was adopted. Patients who received total knee replacement surgery between 2007 and 2008 in any hospital in Taiwan were included. After adjusting for patient, physician, and hospital characteristics, a restricted cubic spline regression model was used to identify optimal surgeon- and hospital-volume thresholds. Further, a patient-level mixed effect model was conducted to test the respective relationships between these thresholds and 30-day readmission.
A total of 30,828 patients who had received their surgeries from 1,468 surgeons in 437 hospitals were included in this study. Thresholds of 50 cases a year for surgeons and 75 cases a year for hospitals were identified using a restricted cubic spline regression model. However, only the surgeon volume threshold was associated with 30-day readmission using a patient-level mixed effect model after adjusting for patient-, surgeon- and hospital-level covariates.
According to the results of the restricted cubic spline models, the optimal volume thresholds for surgeons and hospitals are 50 cases and 75 cases a year, respectively. However, only the surgeon volume threshold is associated with 30-day readmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Photocatalytic hydrogen evolution from natural seawater faces the severe challenges of abundant salts, which adsorb on the active sites and result in undesirable side reactions and photocatalyst ...poisoning. Herein, a series of main‐chain‐engineered discontinuously conjugated polymer (DCP) photocatalysts is presented with bifunctional crown ether (CE) structures for hydrogen evolution from seawater. The hydrophilic CE can significantly inhibit the aggregation of DCPs induced by salts. Meanwhile, cyclic CE can effectively adsorb cations to uncover the active sites to increase their interaction with protons, which can increase the hydrogen evolution rates and significantly reduce the efficiency roll‐off in natural seawater. Through atomistic studies, the formation of hydrogen bonds with bifunctional CE is elucidated and further analysis of the microscale mechanisms is also conducted using molecular dynamics and ab initio techniques. This work suggests that CE‐based polymer has the potential to enhance its ability to produce hydrogen through photocatalysis using seawater.
The first example of incorporating crown ether structure into polymer photocatalysts is demonstrated via a main‐chain‐engineering strategy. The innovative approach significantly reduces ion adsorption on the active sites, resulting in less hydrogen evolution reaction (HER) roll‐off in natural seawater. P‐8CE, in particaular, shows remarkable results with 200% and 258% higher HER than the model photocatalyst, PCzDBTO, in pure water and natural seawater, respectively.
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