Oral Administration Properties Evaluation of Three Milk-derived Extracellular Vesicles Based on Ultracentrifugation Extraction Methods.

Milk-derived extracellular vesicles (M-EVs) are low-cost, can be prepared in large quantities, and can cross the gastrointestinal barrier for oral administration. However, the composition of milk is complex, and M-EVs obtained by different extraction methods may affect their oral delivery. Based on this, we propose a new method for extracting M-EVs based on cryogenic freezing treatment (Cryo-M-EVs) and compare this method with the previously reported acetic acid treatment (Acid-M-EVs) method and the conventional ultracentrifugation method (Ulltr-M-EVs). The new method simplifies the pretreatment step and achieves 25-fold and 2-fold higher yields than Acid-M-EVs and Ulltr-M-EVs. And it was interesting to note that Cryo-M-EVs and Acid-M-EVs had higher cellular uptake efficiency, and Cryo-M-EVs presented the best transepithelial transport effect. After oral administration of the three M-EVs extracted by three methods in mice, Cryo-M-EVs effectively successfully crossed the gastrointestinal barrier and achieved hepatic accumulation, whereas Acid-M-EVs and Ultr-M-EVs mostly resided in the intestine. The M-EVs obtained by the three extraction methods showed a favorable safety profile at the cellular as well as animal level. Therefore, when M-EVs obtained by different extraction methods are used for oral drug delivery, we can utilize their accumulation properties at different sites to better deal with different diseases. This article is protected by copyright. All rights reserved.

Effect of different molecular weight ß-glucan hydrated with highland barley protein on the quality and in vitro starch digestibility of whole wheat bread.

Whole wheat bread has high nutritional value, but it has inferior baking quality and high glycemic index, which needs to be improved by methods such as adding protein and ß-glucan. This study investigated the effects of ß-glucan and highland barley protein of different molecular weights (2 × 104, 1 × 105, and 3 × 105 Da) and different hydrate methods (pre-hydrate and not pre-hydrate) on the characteristics of whole wheat dough and bread. The mixing properties and rheological properties demonstrated that ß-glucan pre-hydrated with highland barley protein were able to reduce the dough tan δ, reduce the dough viscoelasticity, while enhance the gluten network structure and dough deformation resistance. Compared to the control sample, the medium molecular weight pre-hydrate bread had a better specific volume of 3.21 mL/g, lower hardness of 527.28 g. In vitro starch digestion characteristics and ATR-FTIR showed that low and high molecular weight pre-hydrate increased the short-range ordered structure of starch and reduced the starch digestibility, while not pre-hydrated medium molecular weight hydrate had the lowest level of starch digestibility.

A systematic review and meta-analysis of the effectiveness of primary thromboprophylaxis in acute lymphoblastic leukemia during early-phase therapy including asparaginase or its prolonged form.

Asparaginase is essential in the initial management of acute lymphoblastic leukemia (ALL) but frequently leads to venous thromboembolism (VTE). Using anticoagulants for primary VTE prevention has been studied with no consensus. We conducted a systematic literature search in PubMed, Scopus, and Web of science and performed random-effect meta-analysis using Mantel-Haenszel method in RevMan 5.4 to analyze primary pharmacological thromboprophylaxis during asparaginase treatment in early-phase (induction, consolidation, or intensification phase) therapy in patients with ALL with all ages and followed with subgroup analysis by age. Meta-analysis of 13 articles describing the effect of antithrombin supplementation in 1375 patients showed that antithrombin prophylaxis decreases the risk of VTE by 43% (RR, 0.57; 95% CI, 0.38 - 0.83; p=0.004), with mild heterogeneity (I2=35%, p=0.10) and moderate certainty by GRADE. 8 articles included for meta-analysis of low-molecular weight heparin (LMWH) treatment in 612 patients showed that it decreased the risk of VTE by nearly 40% (RR, 0.61; 95% CI, 0.45 - 0.81; p=0.00081), with minimal heterogeneity (I2=14%, p=0.31) but low certainty. Subgroup analysis showed that only prophylaxis with antithrombin supplementation significantly decreased the VTE rate in adult patients with moderate certainty. In pediatric patients, one nonrandomized prospective study showed that LMWH combined with antithrombin has a better thromboprophylaxis effect than antithrombin alone. In the PREVAPIX-ALL trial, prophylaxis with direct factor Xa inhibitor Apixaban did not benefit children younger than 18 years except for cases of obesity. We concluded that thromboprophylaxis with antithrombin is effective in ALL patients older than 18 years during the early phase of therapy, and LMWH combined with antithrombin supplementation might be effective for pediatric patients with ALL. Apixaban is effective in pediatric ALL patients with obesity and needs further study in other high-risk patients.

Regulation of baking quality and starch digestibility in whole wheat bread based on ß-glucans and protein addition strategy: Significance of protein-starch-water interaction in dough.

Whole wheat bread has high nutritional value but is characterized by inferior quality and a high glycemic index. Studies have shown that adding ß-glucans and protein can improve bread quality. This study investigated the effects of added oat ß-glucan, barley ß-glucan, or yeast ß-glucan on protein synergy and whole wheat dough and bread quality. The mixing properties, rheological properties, and scanning electron microscopy observations showed that the addition of ß-glucan promoted the formation of gluten networks, while the synergy between the wheat proteins and ß-glucan resulted in a more robust and stable gluten network and a stronger physical starch envelope. Rapid visco-analysis and thermal property evaluations showed that ß-glucan addition inhibited the thermal degradation, gelatinization, and retrogradation of starch. Based on the bread quality results, it was found the ß-glucan could cause some damage to the bread baking quality. For example, the hardness of samples with oats, barley, and yeast increased to 881.69 g, 952.97 g, and 631.75 g, respectively, compared to samples without ß-glucan (317.49 g), whereas the inclusion of yeast ß-glucan proved to be less detrimental. Protein and ß-glucan both reduced starch digestion to some degree, and showed better synergistic effects, with the lowest estimated glycemic index of 70.08 observed in bread containing added yeast ß-glucan and protein. Therefore, yeast ß-glucan and protein mixtures could be selected as viable formulations for enhancing the quality of whole wheat bread.

Immune cell-derived exosomes as promising tools for cancer therapy.

Exosomes are nanoscale vesicles with a size of 30-150 nm secreted by living cells. They are vital players in cellular communication as they can transport proteins, nucleic acids, lipids, and etc. Immune cell-derived exosomes (imEXOs) have great potential for tumor therapy because they have many of the same functions as their parent cells. Especially, imEXOs display unique constitutive characteristics that are directly involved in tumor therapy. Herein, we begin by the biogenesis, preparation, characterization and cargo loading strategies of imEXOs. Next, we focus on therapeutic potentials of imEXOs from different kinds of immune cells against cancer from preclinical and clinical studies. Finally, we discuss advantages of engineered imEXOs and potential risks of imEXOs in cancer treatment. The advantages of engineered imEXOs are highlighted, including selective killing effect, effective tumor targeting, effective lymph node targeting, immune activation and regulation, and good biosafety.

Middle Meningeal Artery Embolization Combined With Endoscopic Treatment for Chronic Subdural Hematoma.

OBJECTIVE: To explore the clinical feasibility of middle meningeal artery (MMA) embolization combined with endoscopic treatment for new or recurrent chronic subdural hematoma (CSDH). METHODS: Twenty patients with CSDH treated in the Binzhou Medical University Hospital from June 2020 to October 2022 were analyzed retrospectively. The clinical information, prognosis, imaging results, and surgical results of the patients were collected and analyzed. The authors first performed MMA embolization, and then endoscopic treatment of CSDH was performed after successful embolization of MMA. Results: All 20 patients with CSDH were successfully treated with MMA embolization combined with endoscope-assisted evacuation. The symptoms of all patients were relieved, no surgical complications occurred, and no rebleeding and recurrence were found in follow-up computed tomography. CONCLUSION: Middle meningeal artery embolization combined with endoscopic treatment of CSDH has a good clinical effect, and it may prevent postoperative recurrence.

Reducing Co/O Band Overlap through Spin State Modulation for Stabilized High Capability of 4.6 V LiCoO2.

High-voltage LiCoO2 (LCO) attracts great interest because of its large specific capacity, but it suffers from oxygen release, structural degradation, and quick capacity drop. These daunting issues root from the inferior thermodynamics and kinetics of the triggered oxygen anion redox (OAR) at high voltages. Herein, a tuned redox mechanism with almost only Co redox is demonstrated by atomically engineered high-spin LCO. The high-spin Co network reduces the Co/O band overlap, eliminates the adverse phase transition of O3 → H1-3, delays the exceeding of the O 2p band over the Fermi level, and suppresses excessive O → Co charge transfer at high voltages. This function intrinsically promotes Co redox and restrains O redox, fundamentally addressing the issues of O2 release and coupled detrimental Co reduction. Moreover, the chemomechanical heterogeneity caused by different kinetics of Co/O redox centers and the inferior rate performance limited by slow O redox kinetics is simultaneously improved owing to the suppression of slow OAR and the excitation of fast Co redox. The modulated LCO delivers ultrahigh rate capacities of 216 mAh g-1 (1C) and 195 mAh g-1(5C), as well as high capacity retentions of 90.4% (@100 cycles) and 86.9% (@500 cycles). This work sheds new light on the design for a wide range of O redox cathodes.

Codependent failure mechanisms between cathode and anode in solid state lithium metal batteries: mediated by uneven ion flux.

An in-depth understanding of the degradation mechanisms is a prerequisite for developing the next-generation all solid-state lithium metal battery (ASSLMB) technology. Herein, synchrotron X-ray computed tomography (SXCT) together with other probing tools and simulation method were employed to rediscover the decaying mechanisms of LiNi0.8Co0.1Mn0.1O2 (NCM)|Li6PS5Cl (LPSCl)|Li ASSLMB. It reveals that the detachment and isolation of NCM particles cause the current focusing on the remaining active regions of cathode. The extent of Li stripping and the likelihood of Li+ plating into LPSCl facing the active NCM particles becomes higher. Besides, the homogeneity of Li stripping/plating is improved by homogenizing the electrochemical reactions at the cathode side by LiZr2(PO4)3 (LZP) coating. These results suggest a codependent failure mechanism between cathode and anode that is mediated by uneven Li ion flux. This work contributes to a holistic understanding of the degradation mechanisms in ASSLMBs and opens new opportunities for their further optimization and development.

Oxygen Anion Redox Chemistry Correlated with Spin State in Ni-Rich Layered Cathodes.

Despite the low cost and high capacity of Ni-rich layered oxides (NRLOs), their widespread implementation in electric vehicles is hindered by capacity decay and O release. These issues originate from chemo-mechanical heterogeneity, which is mainly related to oxygen anion redox (OAR). However, what to tune regarding OAR in NRLOs and how to tune it remains unknown. In this study, a close correlation between the OAR chemistry and Li/Ni antisite defects is revealed. Experiments and calculations show the opposite effects of aggregative and dispersive Li/Ni antisite defects on the NiO6 configuration and Ni spin state in NRLOs. The resulting broad or narrow spans for the energy bands caused by spin states lead to different OAR chemistries. By tuning the Li/Ni antisite defects to be dispersive rather than aggregative, the threshold voltage for triggering OAR is obviously elevated, and the generation of bulk-O2 -like species and O2 release at phase transition nodes is fundamentally restrained. The OAR is regulated from irreversible to reversible, fundamentally addressing structural degradation and heterogeneity. This study reveals the interaction of the Li/Ni antisite defect/OAR chemistry/chemo-mechanical heterogeneity and presents some insights into the design of high-performance NRLO cathodes.

Shallow magmatic intrusion evolution below La Palma before and during the 2021 eruption.

La Palma, Canary Islands, underwent volcanic unrest which culminated in its largest historical eruption. We study this unrest along 2021 using Interferometric Synthetic Aperture Radar (InSAR) and a new improved interpretation methodology, comparing achieved results with the crustal structure. We reproduce the final phase of La Palma volcanic unrest, highligthing a shallow magma accumulation which begins about 3.5 months before the eruption in a crustal volume charactherized by low density and fractured rocks. Our modeling, together with our improved pictures of the crustal structure, allows us to explain the location and characteristics of the eruption and to detect failed eruption paths. These can be used to explain post-eruptive phenomena and hazards to the local population, such as detected gases anomalies in La Bombilla and Puerto Naos. Our results have implications for understanding volcanic activity in the Canaries and volcano monitoring elsewhere, helping to support decision-making and providing significant insights into urban and infrastructure planning in volcanic areas.

Vitamin E Exerts Neuroprotective Effects in Pentylenetetrazole Kindling Epilepsy via Suppression of Ferroptosis.

Epilepsy is one of the most common chronic neurological diseases. There is increasing evidence for ferroptosis playing an important role in the occurrence and development of epilepsy. Vitamin E is a common fat-soluble antioxidant that can regulate ferroptosis. The aim of this study was to investigate the effects of vitamin E on ferroptosis of hippocampal neurons in epileptic rats. Sixty-four male Sprague-Dawley (SD) rats were randomly divided into control, pentylenetetrazol (PTZ; 35 mg/kg), vitamin E (200 mg/kg) + PTZ, and Ferrostatin-1 (Fer-1; 2.5 µmol/kg) + PTZ groups, with drugs administered intraperitoneally 15 times every other day for 29 days. The behavioral manifestations (epileptic score, latency, and number of seizures in 30 min) and EEG changes were observed and recorded. Nissl staining and electrophysiological recording were used to assess neuronal damage and excitability in the hippocampal CA1 region, respectively. The levels of iron, glutathione (GSH), and malondialdehyde (MDA) in the hippocampus were assessed by spectrophotometry. Immunofluorescence staining was used to detect lipoxygenase 15 (15-LOX) expression. Western blot was used to determine glutathione peroxidase 4 (GPX4) and 15-LOX protein levels. Vitamin E treatment was associated with decreased epileptic grade, seizure latency, and number of seizures in the PTZ-kindled epileptic model. Vitamin E treatment also decreased 15-LOX expression, inhibited MDA and iron accumulation, and increased GPX4 and GSH expression. In conclusion, vitamin E can reduce neuronal ferroptosis and seizures by inhibiting 15-LOX expression.

Patient with Down syndrome and relapsed acute lymphoblastic leukemia with sustained remission despite only partial R3 chemotherapy.

DS-ALL has a higher rate of relapse and treatment-related mortality. The newer immunotherapies are potentially better options. Relapsed ALL with positive MRD has a poor prognosis. Transient long-term remission after ALL relapse due to partial chemotherapy combined severe infection is rare.

Tuning Co2+ Coordination in Cobalt Layered Double Hydroxide Nanosheets via Fe3+ Doping for Efficient Oxygen Evolution.

Inexpensive and efficient electrocatalysts are crucial for the development and practical application of energy conversion and storage technologies. Layered-double-hydroxide (LDH) materials have attracted much attention due to the special layered structure, but their electrocatalytic activity and stability are still limited. Herein, we propose to tune Co2+ occupancy and coordination in cobalt-based LDH nanosheets via Fe3+ doping for efficient and stable electrocatalysis for oxygen evolution reaction (OER). It is found that Fe doping regulates the occupancy and coordination of Co2+ in CoO4 tetrahedrons and CoO6 octahedrons of Co-LDHs. Through density functional theory calculation, we also clarified that Fe3+ not only modulated the Co2+ coordination but also functioned as an added catalytic active site. LDH nanosheets with a Co/Fe ratio of 5:1 show a low OER overpotential, much better than the commercial IrO2, owing to the modulation of Fe3+ doping on the crystal and electronic structures. After appropriate incorporation of Fe3+, the almost inactive octahedral coordinated Co2+ is significantly activated with a partial deletion of tetrahedral coordinated Co2+, which greatly boosts the overall electrocatalytic activity. This study offers some new insights into tuning the crystal and electronic structures of LDHs by lattice doping to achieve high-efficiency electrocatalysis for OER.

Detection of volcanic unrest onset in La Palma, Canary Islands, evolution and implications.

La Palma island is one of the highest potential risks in the volcanic archipelago of the Canaries and therefore it is important to carry out an in-depth study to define its state of unrest. This has been accomplished through the use of satellite radar observations and an original state-of-the-art interpretation technique. Here we show the detection of the onset of volcanic unrest on La Palma island, most likely decades before a potential eruption. We study its current evolution seeing the spatial and temporal changing nature of activity at this potentially dangerous volcano at unprecedented spatial resolutions and long time scales, providing insights into the dynamic nature of the associated volcanic hazard. The geodetic techniques employed here allow tracking of the fluid migration induced by magma injection at depth and identifying the existence of dislocation sources below Cumbre Vieja volcano which could be associated with a future flank failure. Therefore they should continue being monitored using these and other techniques. The results have implications for the monitoring of steep-sided volcanoes at oceanic islands.

A comprehensive study of the multiple effects of Y/Al substitution on O3-type NaNi0.33Mn0.33Fe0.33O2 with improved cycling stability and rate capability for Na-ion battery applications.

O3-NaNi0.33Mn0.33Fe0.33O2 layered oxide has attracted increasing attention as one of the most promising materials for Na-ion battery applications due to air stability and environmental friendliness, but the complex phase transitions and inferior cycling stability are extremely challenging to overcome. Cation substitution has been widely used to stabilize crystal structures and improve electrochemical performance for SIBs. Based on past experimental results, it was discovered that the transition metal-oxygen bond energy of the introduced dopant is an important factor for optimizing electrochemical performance. In this study, we validated our hypothesis that yttrium (Y)-which possesses high bond energy for oxygen-is most likely to be an ideal doping element by conducting a comparative study of substituting Mn in O3-NaNi0.33Mn0.33Fe0.33O2 layered oxide with aluminum (Al) and Y through elemental doping. As hypothesized, the electrochemical properties of NaNi0.33Mn0.33Fe0.33O2 have increased markedly by introducing a small amount of Y and Al, and the Y-doped materials showed superior rate performance and cycling stability due to enhanced Na+ diffusion reaction kinetics and layered structure stability. Furthermore, the substitution of Y for Mn can improve thermal stability and alleviate phase transformations. The improvement mechanism of Y substitution can be attributed to a larger d-spacing and stronger metal-oxygen bond. These results suggest that structural modulation is an effective strategy to reinforce electrochemical properties of layered oxides and provides some guidance about designing promising electrode materials.

Ibuprofen Exerts Antiepileptic and Neuroprotective Effects in the Rat Model of Pentylenetetrazol-Induced Epilepsy via the COX-2/NLRP3/IL-18 Pathway.

Epilepsy is one of the most common diseases of the central nervous system. Recent studies have shown that a variety of inflammatory mediators play a key role in the pathogenesis of the disease. Ibuprofen (IBP) is a well-known anti-inflammatory agent that reduces the neuroinflammatory response and neuronal damage. In this study, we examined the effect of IBP in a rat model of pentylenetetrazol (PTZ)-induced chronic epilepsy. PTZ injection was given a total of 15 times on alternate days (over a period of 29 days) to induce epilepsy. The effects of IBP were evaluated by behavioral observation, EEG recording, Nissl staining, immunohistochemistry, Western blot analysis, and electrophysiological recording. The results showed that IBP alone affected the expression of cyclooxygenase-2 (COX-2) and neuronal excitability but did not cause epilepsy. IBP reduced seizure scores in the PTZ-treated rats, and it minimized the loss of hippocampal neurons. In addition, IBP decreased the secretion of COX-2, inhibited the activation of the NOD-like receptor 3 inflammasome, and reduced the secretion of the inflammatory cytokine interleukin-18. Furthermore, the results of whole-cell patch-clamp revealed that IBP affected action potential properties, including frequency, latency and duration in epileptic rats, suggesting that it may impact neuronal excitability. These effects of IBP may underlie its antiepileptic and neuroprotective actions.