The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broad-spectrum protection against the initial infection and thereby curb the ...transmission potential. Here, we designed a chimeric triple-RBD immunogen, 3Ro-NC, harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold. 3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern. Notably, intranasal immunization with 3Ro-NC plus the mucosal adjuvant KFD (3Ro-NC + KFDi.n) elicits coordinated mucosal IgA and higher neutralizing antibody specificity (closer antigenic distance) against the Omicron variant. In Omicron-challenged human ACE2 transgenic mice, 3Ro-NC + KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung (85.7-fold) and the nasal turbinate (13.6-fold). Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies. Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection, pathology and transmission potential.
A series of berberine derivatives were synthesized by introducing substituted benzyl groups at C-9. All these synthesized compounds (4a–4m) were screened for their in vitro antibacterial activity ...against four Gram-positive bacteria and four Gram-negative bacteria and evaluated for their antifungal activity against three pathogenic fungal strains. All these compounds displayed good antibacterial and antifungal activities, compared to reference drugs including Ciprofloxacin and Fluconazole; Compounds 4f, 4g, and 4l showed the highest antibacterial and antifungal activities. Moreover, all the synthesized compounds were docked into topoisomerase II-DNA complex, which is a crucial drug target for the treatment of microbial infections. Docking results showed that H-bond, π-π stacked, π-cationic, and π-anionic interactions were responsible for the strong binding of the compounds with the target protein-DNA complex.
A formal enantioselective total synthesis of bisdehydroneostemoninine employing L-glutamic acid as the chiral pool is described. The key features of the synthesis include regioselective and ...enantioselective opening the chiral epoxide with dimethylsulfonium methylide and tandem Friedel-Crafts cyclization followed by lactonization to form the 5-7-5 tricyclic core of the target stemona alkaloids. The synthetic route provides opportunities to explore the biological behavior of enantiopure bisdehydroneostemoninine.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The synergetic biological effect of scaffolds with biomimetic properties including the ECM micro-architecture and intestinal macro-mechanical properties on intestinal models
in vitro
remains unclear. ...Here, we investigate the profitable role of biomimetic scaffolds on 3D intestinal epithelium models. Gelatin/bacterial cellulose nanofiber composite scaffolds crosslinked by the Maillard reaction are tuned to mimic the chemical component, nanofibrous network, and crypt architecture of intestinal ECM collagen and the stability and mechanical properties of intestinal tissue. In particular, scaffolds with comparable elasticity and viscoelasticity of intestinal tissue possess the highest biocompatibility and best cell proliferation and differentiation ability, which makes the intestinal epithelium models closest to their counterpart intestinal tissues. The constructed duodenal epithelium models and colon epithelium models are utilized to assess the immunobiotics-host interactions, and both of them can sensitively respond to foreign microorganisms, but the secretion levels of cytokines are intestinal cell specific. The results demonstrate that probiotics alleviate the inflammation and cell apoptosis induced by
Escherichia coli
, indicating that probiotics can protect the intestinal epithelium from damage by inhibiting the adhesion and invasion of
E. coli
to intestinal cells. The designed biomimetic scaffolds can serve as powerful tools to construct
in vitro
intestinal epithelium models, providing a convenient platform to screen intestinal anti-inflammatory components and even to assess other physiological functions of the intestine.
Intestinal epithelium models based on biomimetic scaffolds with an ECM micro-architecture and intestinal macro-elasticity are close to their counterpart intestinal tissues, serving as powerful
in vitro
tools to assess the immunobiotics-host interactions.
Four kinds of amino functionalized well-designed core–shell molecularly imprinted magnetic polymer microspheres (nFe3O4@NH2MIP) were controlledly synthesized. Batch adsorption experiments showed that ...the nFe3O4@NH2MIP possessed specific selectivity and high affinity to the template 2,4,6-TCP over other structure analogs.
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•Core–shell structured amino functionalized molecularly imprinted magnetic polymers (nFe3O4@NH2MIP).•Surface imprinting cavities favorable the mass transfer to accelerate the adsorption process.•Potential reusable adsorbents for selective removal of 2,4,6-TCP in environmental water.
Four kinds of novel amino functionalized core–shell molecularly imprinted magnetic polymers (nFe3O4@NH2MIP) were synthesized via suspension polymerization and surface imprinting technique. Different amines, i.e., ethylenediamine (EDA), diethylenetriamine (DETA), triethylentetramine (TETA) and tetraethylenepentamine (TEPA), were used for surface grafting. The obtained nFe3O4@NH2MIP were named as nFe3O4@EDAMIP, nFe3O4@DETAMIP, nFe3O4@TETAMIP and nFe3O4@TEPAMIP, respectively. The as-prepared nFe3O4@NH2MIP were fully characterized. Batch adsorption experiments of nFe3O4@NH2MIP showed that specific selectivity and remarkable adsorption capacity to 2,4,6-trichlorophenol (2,4,6-TCP) can be obtained. Mechanism studies suggested that the excellent adsorption properties were closely relied on hydrogen bonding, which are strongly related to the amino groups grafted on the surface of the magnetic polymers. Kinetic studies showed that the adsorption of 2,4,6-TCP by nFe3O4@NH2MIP followed pseudo-second-order models, with the adsorption rate constants, k2, at 0.00394–0.02209g/(mgmin), suggesting chemisorption processes. Both the adsorption rate constants (k2) and the initial adsorption rates (k2qe2) of the nFe3O4@NH2MIP were higher than those of the non-molecularly imprinted magnetic polymers (nFe3O4@NH2NIP). The existing of the surface imprinting cavities might be favorable for the mass transfer to accelerate the adsorption process, thus, leading to a faster adsorption process. Thermodynamic studies suggested that the adsorption processes fit the Freundlich isotherms well. The adsorption capacity of nFe3O4@NH2MIP was found to be 872.8, 880.5, 888.3, 898.7mg/g with the imprinting factor (α) toward 2,4,6-TCP at 2.68, 2.31, 2.22, 2.03, for nFe3O4@EDAMIP, nFe3O4@DETAMIP, nFe3O4@TETAMIP and nFe3O4@TEPAMIP, respectively. Three kinds of real environmental water samples were treated by the as prepared nFe3O4@NH2MIP. The results proved that these materials could be a series of great potential reusable adsorbents for selective removal of 2,4,6-TCP in environmental water.
Depression is one of the most prevalent and serious mental disorders with a worldwide significant health burden. Metabolic abnormalities and disorders in patients with depression have attracted great ...research attention. Thirty-six metabolic biomarkers of clinical plasma metabolomics were detected by platform technologies, including gas chromatography–mass spectrometry (GC–MS), liquid chromatography–mass spectrometry (LC–MS) and proton nuclear magnetic resonance (
1
H-NMR), combined with multivariate data analysis techniques in previous work. The principal objective of this study was to provide valuable information for the pathogenesis of depression by comprehensive analysis of 36 metabolic biomarkers in the plasma of depressed patients. The relationship between biomarkers and enzymes were collected from the HMDB database. Then the metabolic biomarkers-enzymes interactions (MEI) network was performed and analyzed to identify hub metabolic biomarkers and enzymes. In addition, the docking score-weighted multiple pharmacology index (
DSWMP
) was used to assess the important pathways of hub metabolic biomarkers involved. Finally, validated these pathways by published literature. The results show that stearic acid, phytosphingosine, glycine, glutamine and phospholipids were important metabolic biomarkers. Hydrolase, transferase and acyltransferase involve the largest number of metabolic biomarkers. Nine metabolite targets (TP53, IL1B, TNF, PTEN, HLA-DRB1, MTOR, HRAS, INS and PIK3CA) of potential drug proteins for treating depression are widely involved in the nervous system, immune system and endocrine system. Seven important pathways, such as PI3K-Akt signaling pathway and mTOR signaling pathway, are closely related to the pathology mechanisms of depression. The application of important biomarkers and pathways in clinical practice may help to improve the diagnosis of depression and the evaluation of antidepressant effect, which provides important clues for the study of metabolic characteristics of depression.
During downstream drifting in high-speed steams, semi-buoyant fish eggs can run onto rocks, boats, and other surfaces. This will result in the abrupt and severe collision shock to the fish eggs, ...causing damage to fish eggs and potentially leading to their death. For protection of fish stocks and river management, it is crucial to understand the impact of collision shock on their hatching and to clarify the upper threshold of collision velocity. Through an indoor free-fall experiment, we quantified the influences of collision shock on semi-buoyant fish eggs. We discovered that, when fish eggs collided with a rock at a speed of 4.4 m/s, about 70% of the eggs did not successfully hatch. Forty-five percent of the egg envelopes were broken when the collision velocity was 4.4 m/s and collided with water. Development stage, particularly when the eggs were at the cell cleavage stage, was the most susceptible factor to collision shock. Our results offer new insights for preserving fish stocks in high-speed streams and can be used to inform river management strategies.
•Collision shock on the hatching of semi-buoyant fish eggs was quantified.•Seventy percent of the eggs didn’t hatch after a collision with a rock at 4.4 m/s.•Collision strategies can help to regulate the population of certain fish species.
To investigate the effect of total pelvic floor reconstruction with a six-arm mesh in the treatment of pelvic organ prolapse.
This is a retrospective observational cohort study. A total of 368 ...patients with pelvic organ prolapse underwent pelvic floor reconstruction surgery. Patients were categorized by the type of surgical mesh: 176 patients received a six-arm mesh and 192 patients received an anteroposterior approach mesh. The 1-year effect of the two groups was compared. The Pelvic Floor Distress Inventory Questionnaire (PFDI-20), Colorectal-Anal Distress Inventory (CRADI-8) and the Pelvic Organ Prolapse Quantitation (POP-Q) staging were used for evaluation. The incidence of complications was recorded. A cure standard was registered by a POP-Q score of grade I or below. A P value <0.05 indicates the difference is statistically significant.
There was no recurrence documented in the patients; the cure rate was 100% in both groups. After surgery, the length of the vagina in the six-arm mesh group was longer than that of the control group at 6 months and 12 months, respectively (
< 0.05). The six-arm mesh group had lower PFDI-20 and CRADI-8 scores after surgery than those of the control group at 6 and 12 months, respectively (
< 0.05). Pelvic floor and rectal dysfunction symptom improvement were superior in the six-arm mesh group compared with the control group. After surgery, the Female Sexual Function Inventory (FSFI) score of the six-arm mesh group was superior to that of the control group at 6 and 12 months, respectively (
< 0.05). The incidence of complications in the six-arm mesh group was lower than that of the control group (
< 0.05).
The total pelvic floor reconstruction using six-arm mesh has the same healing rate as anteroposterior approach mesh surgery, and it is better than traditional surgery in improving subjective symptoms and reducing postoperative complications.
Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic. Here, we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal ...vaccination of a triple receptor-binding domain (RBD) scaffold protein (3R-NC) adjuvanted with a flagellin protein (KFD) (3R-NC + KFDi.n). In mice, the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year. This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG- and IgA-producing plasma cells, alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant. Based upon these preclinical findings, an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2 (IAV) vaccine. With a favorable safety profile, the 3R-NC + KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions. To meet the challenge of frequently emerged variants, we further designed an updated triple-RBD scaffold protein with mutated RBD combinations, which can induce adaptable antibody responses to neutralize the newly emerging variants, including JN.1. Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.
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