Long-term stability and immunogenicity of lipid nanoparticle COVID-19 mRNA vaccine is affected by particle size.

Messenger ribonucleic acid (mRNA) technology has been rapidly applied for the development of the COVID-19 vaccine. However, naked mRNA itself is inherently unstable. Lipid nanoparticles (LNPs) protect mRNAs from extracellular ribonucleases and facilitate mRNA trafficking. For mRNA vaccines, antigen-presenting cells utilize LNPs through uptake to elicit antigen-specific immunity. There are reports on the impact of various physical characteristics of LNPs, particularly those with sizes less than 200 nm, especially 50 to 150 nm, on the overall stability and protective efficacy of mRNA vaccines. To address this, a single change in the size of LNPs using the same mRNA stock solution was assessed for the physicochemical characterization of the resulting mRNA-LNPs vaccine, along with the evaluation of their protective efficacy. Particles of smaller sizes generally disperse more effectively in solutions, with minimized occurrence of particle precipitation and aggregation. Here, we demonstrate that the vaccine containing 80-100 nm mRNA-LNPs showed the best stability and protection at 4°C and -20°C. Furthermore, we can conclude that freezing the vaccine at -20°C is more appropriate for maintaining stability over the long term. This effort is poised to provide a scientific basis for improving the quality of ongoing mRNA vaccine endeavors and providing information on the development of novel products.

Magnetic quaternary ammonium polymer bearing porous agarose for selective extraction of Aristolochic acids in the plasma.

Aristolochic acids (AAs) naturally occurring in the herbal genus Aristolochia are associated with a high risk of kidney failure, multiple tumors and cancers. However, approaches with high selectivity and rapidity for measuring AAs in biological samples are still inadequate. Inspired by the mechanism of AAs-induced nephrotoxicity, we designed a hybrid magnetic polymer-porous agarose (denoted as MNs@SiO2M@DNV-A), mimicking the effect of basic and aromatic residues of organic anion transporter 1 (OAT1) for efficient enriching aristolochic acid I (AA I) and aristolochic acid II (AA II) in the plasma. The monomers of vinylbenzyl trimethylammonium chloride (VBTAC), N-vinyl-2-pyrrolidinone (NVP) and divinylbenzene (DVB) were employed to construct the polymer layer, which provided a selective adsorption for AAs by multiple interactions. The porous agarose shell contributed to remove interfering proteins in the plasma samples. A magnetic solid-phase extraction (MSPE) based on the proposed composite enhanced the selectivity toward AA I and AA II in the plasma samples. In combination of HPLC analysis, the proposed method was proved to be applicable to fast and specific quantification of AAs in blood samples, which was characterized by a good linearity, high sensitivity, acceptable recovery, excellent repeatability and satisfactory reusability.

Study on load transfer mechanisms and impact on adjacent railway subgrade within loess regions.

Clarifying load transfer mechanism and the influence of the widening of a newly-built railway is the premise for the construction of adjacent project in loess region. This paper uses monitoring datas obtained from three sections in different stages to analyze the distribution laws of load exert on piles and soil between piles, investigates the variation laws of filling height on the earth pressure at different excavation steps and elucidates the influence of the filling height of newly built subgrade on the existing subgrade. In addition, a fitting formula y = a(1-e-bx) + cx is proposed to describe the relationship between the ratio of the additional displacement to the filling height, which is applicable for similar projects.

Study on chromatin regulation patterns of expression vectors in the PhiC31 integration site.

The PhiC31 integration system allows for targeted and efficient transgene integration and expression by recognizing pseudo attP sites in mammalian cells and integrating the exogenous genes into the open chromatin regions of active chromatin. In order to investigate the regulatory patterns of efficient gene expression in the open chromatin region of PhiC31 integration, this study utilized Ubiquitous Chromatin Opening Element (UCOE) and activating RNA (saRNA) to modulate the chromatin structure in the promoter region of the PhiC31 integration vector. The study analysed the effects of DNA methylation and nucleosome occupancy changes in the integrated promoter on gene expression levels. The results showed that for the OCT4 promoter with moderate CG density, DNA methylation had a smaller impact on expression compared to changes in nucleosome positioning near the transcription start site, which was crucial for enhancing downstream gene expression. On the other hand, for the SOX2 promoter with high CG density, increased methylation in the CpG island upstream of the transcription start site played a key role in affecting high expression, but the positioning and clustering of nucleosomes also had an important influence. In conclusion, analysing the DNA methylation patterns, nucleosome positioning, and quantity distribution of different promoters can determine whether the PhiC31 integration site possesses the potential to further enhance expression or overcome transgene silencing effects by utilizing chromatin regulatory elements.

Full-body pose reconstruction and correction in virtual reality for rehabilitation training.

Existing statistical data indicates that an increasing number of people now require rehabilitation to restore compromised physical mobility. During the rehabilitation process, physical therapists evaluate and guide the movements of patients, aiding them in a more effective recovery of rehabilitation and preventing secondary injuries. However, the immutability of mobility and the expensive price of rehabilitation training hinder some patients from timely access to rehabilitation. Utilizing virtual reality for rehabilitation training might offer a potential alleviation to these issues. However, prevalent pose reconstruction algorithms in rehabilitation primarily rely on images, limiting their applicability to virtual reality. Furthermore, existing pose evaluation and correction methods in the field of rehabilitation focus on providing clinical metrics for doctors, and failed to offer patients efficient movement guidance. In this paper, a virtual reality-based rehabilitation training method is proposed. The sparse motion signals from virtual reality devices, specifically head-mounted displays hand controllers, is used to reconstruct full body poses. Subsequently, the reconstructed poses and the standard poses are fed into a natural language processing model, which contrasts the difference between the two poses and provides effective pose correction guidance in the form of natural language. Quantitative and qualitative results indicate that the proposed method can accurately reconstruct full body poses from sparse motion signals in real-time. By referencing standard poses, the model generates professional motion correction guidance text. This approach facilitates virtual reality-based rehabilitation training, reducing the cost of rehabilitation training and enhancing the efficiency of self-rehabilitation training.

Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL.

The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard of care chemotherapy (SC). Here we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n=43; SC, n=48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery rates were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5] P=0.0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8], P=0.0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P<0.0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.clinicaltrials.gov as no. NCT01564784.

Engineering marine phospholipid nanoliposomes via glycerol-infused proliposomes: Mechanisms, strategies, and versatile applications in scalable food-grade nanoliposome production.

This study presents a novel approach using polyol-based proliposome to produce marine phospholipids nanoliposomes. Proliposomes were formulated by blending glycerol with phospholipids across varying mass ratios (2:1 to 1:10) at room temperature. Analysis employing polarized light microscopy, FTIR, and DSC revealed that glycerol disrupted the stacked acyl groups within phospholipids, lowering the phase transition temperature (Tm). Krill oil phospholipids (KOP) proliposomes exhibited superior performance in nanoliposomes formation, with a mean diameter of 125.60 ± 3.97 nm, attributed to the decreased Tm (-7.64 and 7.00 °C) compared to soybean phospholipids, along with a correspondingly higher absolute zeta potential (-39.77 ± 1.18 mV). The resulting KOP proliposomes demonstrated liposomes formation stability over six months and under various environmental stresses (dilution, thermal, ionic strength, pH), coupled with in vitro absorption exceeding 90 %. This investigation elucidates the mechanism behind glycerol-formulated proliposomes and proposes innovative strategies for scalable, solvent-free nanoliposome production with implications for functional foods and pharmaceutical applications.

Theoretical Study of Electrocatalytic CO2 Reduction Mechanism on Typical MXenes under Realistic Conditions.

MXenes are a revolutionary class of two-dimensional materials that have been recently demonstrated to exhibit promising capability of electrocatalytic CO2 reduction reaction (CO2RR) in theory and experiment. In electrocatalytic reactions, the active phases, the mechanism, and the performance can be greatly influenced by electrochemical conditions such as applied electrode potential, pH, and electrolyte. Therefore, in this first-principles study, the stable surface structures of three typical MXenes (V2C, Mo2C, and Ti3C2) with variation of electrocatalytic conditions were determined by the Pourbaix phase diagrams. Additionally, the reaction mechanism for CO2RR toward C1 products was investigated based on the thermal dynamically stable phases. The computation revealed that surfaces of all three MXenes are dominated by H* termination throughout the practical CO2RR electrochemical condition ranges. Meanwhile, the bicarbonate ions, which serve as the major electrolyte in CO2RR, show thermal dynamic unfavorability to adsorb on the surfaces. Among the three types of MXenes, V2CH exhibits higher activity in generating CO and HCOOH through the CO2RR, while Mo2CH exhibits higher activity in producing HCHO, CH3OH, and CH4. This comprehensive study provides crucial insights into the mechanism of electrocatalytic CO2RR on MXenes under realistic electrochemical conditions.

Optimized OTSU Segmentation Algorithm-Based Temperature Feature Extraction Method for Infrared Images of Electrical Equipment.

Infrared image processing is an effective method for diagnosing faults in electrical equipment, in which target device segmentation and temperature feature extraction are key steps. Target device segmentation separates the device to be diagnosed from the image, while temperature feature extraction analyzes whether the device is overheating and has potential faults. However, the segmentation of infrared images of electrical equipment is slow due to issues such as high computational complexity, and the temperature information extracted lacks accuracy due to the insufficient consideration of the non-linear relationship between the image grayscale and temperature. Therefore, in this study, we propose an optimized maximum between-class variance thresholding method (OTSU) segmentation algorithm based on the Gray Wolf Optimization (GWO) algorithm, which accelerates the segmentation speed by optimizing the threshold determination process using OTSU. The experimental results show that compared to the non-optimized method, the optimized segmentation method increases the threshold calculation time by more than 83.99% while maintaining similar segmentation results. Based on this, to address the issue of insufficient accuracy in temperature feature extraction, we propose a temperature value extraction method for infrared images based on the K-nearest neighbor (KNN) algorithm. The experimental results demonstrate that compared to traditional linear methods, this method achieves a 73.68% improvement in the maximum residual absolute value of the extracted temperature values and a 78.95% improvement in the average residual absolute value.

Highly Selective Lithium Transport through Crown Ether Pillared Angstrom Channels.

Biological ion channels use the synergistic effects of various strategies to realize highly selective ion sieving. For example, potassium channels use functional groups and angstrom-sized pores to discriminate rival ions and enrich target ions. Inspired by this, we constructed a layered crystal pillared by crown ether that incorporates these strategies to realize high Li+ selectivity. The pillared channels and crown ether have an angstrom-scale size. The crown ether specifically allows the low-barrier transport of Li+ . The channels attract and enrich Li+ ions by up to orders of magnitude. As a result, our material sieves Li+ out of various common ions such as Na+ , K+ , Ca2+ , Mg2+ and Al3+ . Moreover, by spontaneously enriching Li+ ions, it realizes an effective Li+ /Na+ selectivity of 1422 in artificial seawater where the Li+ concentration is merely 25 µM. We expect this work to spark technologies for the extraction of lithium and other dilute metal ions.

Coupling process for preparing biomass-based furfural and levulinic acid from corncob: Extraction, green chemistry and techno-economic assessment.

The purpose of this study is to design and investigate two coupling processes for acid-catalyzed hydrolysis of corncob, achieving the simultaneous preparation of biomass-based furfural and levulinic acid (LA). Meanwhile, high concentration and yield of LA were obtained through a situ feeding strategy of pretreated furfural residue with high solids loading (20%, w/v). In Scenario A, 2-methyltetrahydrofuran was selected as the solvent for the LA extraction process compared with the neutralization process in Scenario B. Techno-economic assessment results show that Scenario A is technically feasible and cost-competitive, with an internal rate of return of 21.92%, a net present value of 121 million US dollars, a carbon efficiency of 72%, an environmental factor of 4.38, and a process mass intensity of 32.19. This study will provide new insights for fully utilizing lignocellulosic biomass to prepare renewable energy resources, comprehensively evaluating the economic feasibility, and promoting green and low-carbon development.

Expression mapping of GREM1 and functional contribution of its secreting cells in the brain using transgenic mouse models.

GREMLIN1 (GREM1) is a secreted protein that antagonizes bone morphogenetic proteins (BMPs). While abnormal GREM1 expression has been reported to cause behavioral defects in postpartum mice, the spatial and cellular distribution of GREM1 in the brain and the influence of the GREM1-secreting cells on brain function and behavior remain unclear. To address this, we designed a genetic cassette incorporating a 3×Flag-TeV-HA-T2A-tdTomato sequence, resulting in the creation of a novel Grem1Tag mouse model, expressing an epitope tag (3×Flag-TeV-HA-T2A) followed by a fluorescent reporter (tdTomato) under the control of the endogenous Grem1 promoter. This design facilitated precise tracking of the cell origin and distribution of GREM1 in the brain using tdTomato and Flag (or HA) markers, respectively. We confirmed that the Grem1Tag mouse exhibited normal motor, cognitive, and social behaviors at postnatal 60 days (P60), compared with C57BL/6J controls. Through immunofluorescence staining, we comprehensively mapped the distribution of GREM1-secreting cells across the central nervous system. Pervasive GREM1 expression was observed in the cerebral cortex (Cx), medulla, pons, and cerebellum, with the highest levels in the Cx region. Notably, within the Cx, GREM1 was predominantly secreted by excitatory neurons, particularly those expressing calcium/calmodulin-dependent protein kinase II alpha (Camk2a), while inhibitory neurons (parvalbumin-positive, PV+) and glial cells (oligodendrocytes, astrocytes, and microglia) showed little or no GREM1 expression. To delineate the functional significance of GREM1-secreting cells, a selective ablation at P42 using a diphtheria toxin A (DTA) system resulted in increased anxiety-like behavior and impaired memory in mice. Altogether, our study harnessing the Grem1Tag mouse model reveals the spatial and cellular localization of GREM1 in the mouse brain, shedding light on the involvement of GREM1-secreting cells in modulating brain function and behavior. Our Grem1Tag mouse serves as a valuable tool for further exploring the precise role of GREM1 in brain development and disease.

Light-Augmented Multi-ion Interaction in MXene Membrane for Simultaneous Water Treatment and Osmotic Power Generation.

The mixing of wastewater and natural water releases abundant osmotic energy. Harvesting this energy could significantly reduce the energy and economic cost of water treatment, leading to sustainable wastewater treatment technology. Yet, such energy harvesting is highly challenging because it requires a material that is highly permeable to nontoxic ions while rejecting toxic ions in wastewater to reach high power density and prevent environmental pollution. In this work, we demonstrate that a light-augmented biomimetic multi-ion interaction in an MXene membrane can simultaneously realize high permeability of Na+ ions for enhanced osmotic power generation and high selectivity to heavy metal ions up to a ratio of 2050 for wastewater treatment. The Na+ permeability is enhanced by the photothermal effect of the MXene membrane. The transport of heavy metal ions, however, is suppressed because, under angstrom-confinement, heavy metal ions are strongly electrostatically repelled by the increased number of permeating Na+ ions. As a result, the membrane can stably generate osmotic power from simulated industrial wastewater, and the power density can be enhanced by 4 times under light illumination of approximate 1 sun intensity. This work highlights the importance of multi-ion interaction for the transport properties of ionic materials, which remains rarely investigated and poorly understood in previous studies.

Artificial Sodium Channels for Enhanced Osmotic Energy Harvesting.

Inspired by the ion channels of electric eels, we can use biomimetic nanofluidic materials to harvest the osmotic power released by mixing seawater and river water. While biological ion channels have both cation/anion and inter-cation selectivity, previous nanofluidic materials neglected the latter. As a result, NaCl solutions were generally used to simulate river water, ignoring the fact that the dominating cation in river water is typically Ca2+. In this work, we show that the different ionic compositions of seawater and river water can be exploited to improve osmotic power density by employing biomimetic sodium selective materials. Inspired by a range of properties of biological sodium channels, we constructed artificial sodium channels with zeolitic imidazolate framework-65 crystals, which selectively transport Na+ but almost completely block Ca2+. Resultantly, the effective concentration gradient of seawater/river water is dramatically increased by preventing the major cations in the river water from participating in the ion diffusion. As a result, the osmotic power density can be increased by more than 1 order of magnitude. These results should open new avenues to develop high-performance osmotic generators and may advance other applications based on biomimetic ion channels such as neuromorphic information processing.

Comprehensive Analyses of Breads Supplemented with Tannic Acids.

Tannic acid (TA) has been recently considered as a new dough additive for improving the bread-making quality of wheat. However, the effects of TA supplementation on the sensory quality parameters (color, crumb grain structure, and sensory properties) of bread have not been studied. Further, the potential of TA supplementation in bread-making quality improvement has not been evaluated by using commercial flour. In the present study, three commercial wheat flours (namely, XL, QZG, and QZZ) with different gluten qualities were used to evaluate the effects of TA supplementation (in concentrations of 0.1% and 0.3%, respectively). TA supplementation did not change the proximate composition of the breads but increased the volumes and specific volumes of XL and QZG breads. TA supplementation enhanced antioxidant activities, with 0.3% TA significantly increasing the antioxidant capacities of bread made from all three flour samples by approximately four-fold (FRAP method)/three-fold (ABTS method). Positive effects of TA on the reduction in crumb hardness, gumminess, and chewiness were observed in the XL bread, as determined by the texture profile analysis. For the analyses on visual and sensory attributes, our results suggest that TA did not affect the crust color, but only slightly reduced the L* (lightness) and b* (yellowness) values of the crumb and increased the a* (redness) value. TA supplementation also increased the porosity, total cell area, and mean cell area. Satisfactorily, the sensory evaluation results demonstrate that TA-supplemented breads did not exhibit negative sensory attributes when compared to the non-TA-added breads; rather, the attributes were even increased. In summary, TA-supplemented breads generally had not only better baking quality attributes and enhanced antioxidant activities, but, more importantly, presented high consumer acceptance in multiple commercial flour samples. Our results support the commercial potential of TA to be used as a dough improver.

Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial.

This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.

Two-Dimensional Sodium Channels with High Selectivity and Conductivity for Osmotic Power Generation from Wastewater.

Conducting target ions rapidly while rejecting rival ions efficiently is challenging yet highly demanded for ion separation related applications. Two-dimensional (2D) channels are widely used for ion separation, but highly selective 2D channels generally suffer from a relatively low ionic conductivity. Here we report that the 2D vermiculite channels have a Na+ conductivity higher than bulk and at the same time reject heavy metal ions with a selectivity of a few hundreds. Such performance is attributed to the highly electronegative crystal surface and the extremely narrow channel (0.2 nm high), as also supported by the ab initio molecular dynamics simulation. We demonstrate that the highly selective and conductive sodium channels can be utilized to harvest osmotic power from industrial wastewater, achieving a power density of more than 20 W m-2 while preventing pollution from waste heavy metal ions. This work provides a strategy for wastewater utilization as well as treatment. Moreover, the investigation suggests the possibility to break the ionic permeability-selectivity trade-off by combining Ångstrom-scale confinement with proper surface engineering, which could lead to applications that are challenging for previous materials.

Effects of N-acetyl-L-cysteine polysulfides on periodontitis in a mouse model.

BACKGROUND: Polysulfides are reported to be involved in various important biological processes. N-acetyl-l-cysteine polysulfide with 2 sulfane sulfur atoms (NAC-S2) regulates diverse toll-like receptor (TLR) signaling pathways. Here, we aimed to determine the role of NAC-S2 in periodontitis and explore the potential mechanism. METHODS: A periodontitis mouse model was established by ligating the subgingival between the first and second molars in wild-type, TLR4-/- , and Myd88-/- mice. RESULTS: NAC-S2 did not affect the proportion of macrophages (CD11b+ F4/80+ ) or neutrophils (CD11b+ GR-1+ ) in the bone marrow. Mechanically, lipopolysaccharides (LPS), Zymosan A, or poly I: C induced tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1ß expression in bone marrow-derived macrophages (BMDMs) could be inhibited by NAC-S2. On the other hand, NAC-S2 suppressed the phosphorylation levels of IκB-α, p65, and IκB kinase (IKK)-ß induced by LPS in BMDMs, while LPS induced phosphorylation of ERK1/2, p38, and transforming growth factor ß-activated kinase 1 (TAK1) could not be affected by NAC-S2. In wild-type periodontitis mice, NAC-S2 administration decreased the cemento-enamel-junction-alveolar bone crest (CEJ-ABC) distance and the relative mRNA expression of TNF, IL-6, and IL-1ß, while such phenomena could not be observed in TLR4 deficiency or Myd88 deficiency mice. CONCLUSIONS: All of these results indicate that NAC-S2 ameliorates TLR4/NF-κB pathway mediated inflammation in mouse periodontitis model.

Examining the impact of Tetragenococcus halophilus, Zygosaccharomyces rouxii, and Starmerella etchellsii on the quality of soy sauce: a comprehensive review of microbial population dynamics in fermentation.

Soy sauce is a popular fermented seasoning due to its distinct flavor and rich umami taste. Its traditional production involves two stages: solid-state fermentation and moromi (brine fermentation). During moromi, the dominant microbial population in the soy sauce mash changes, which is called microbial succession and is essential for the formation of soy sauce flavor compounds. Research has identified the sequence of succession, starting with Tetragenococcus halophilus, then Zygosaccharomyces rouxii, and lastly, Starmerella etchellsii. Factors such as the environment, microbial diversity, and interspecies relationships drive this process. Salt and ethanol tolerance influence microbial survival, while nutrients in the soy sauce mash support the cells in resisting external stress. Different microbial strains have varying abilities to survive and respond to external factors during fermentation, which impacts soy sauce quality. In this review, we would examine the factors behind the succession of common microbial populations in the soy sauce mash and explore how microbial succession affects soy sauce quality. The insights gained can help better manage the dynamic changes in microbes during fermentation, leading to improved production efficiency.