hUCMSC-derived exosomes protect against GVHD-induced endoplasmic reticulum stress in CD4+ T cells by targeting the miR-16-5p/ATF6/CHOP axis.

Exosomes generated from mesenchymal stem cells (MSCs) are thought to be a unique therapeutic strategy for several autoimmune deficiency illnesses. The purpose of this study was to elucidate the protective effects of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exo) on CD4+ T cells dysfunction during graft-versus-host disease (GVHD) and to identify the underlying processes involved. Here, we showed that hUCMSC-Exo treatment can effectively attenuate GVHD injury by alleviating redox metabolism disorders and inflammatory cytokine bursts in CD4+ T cells. Furthermore, hUCMSC-Exo ameliorate ER stress and ATF6/CHOP signaling-mediated apoptosis in CD4+ T cells and promote the development of CD4+IL-10+ T cells during GVHD. Moreover, downregulating miR-16-5p in hUCMSC-Exo impaired their ability to prevent CD4+ T cells apoptosis and weakened their ability to promote the differentiation of CD4+IL-10+ T cells. Collectively, the obtained data suggested that hUCMSC-Exo suppress ATF6/CHOP signaling-mediated ER stress and apoptosis in CD4+ T cells, enhance the differentiation of CD4+IL-10+ T cells, and reverse the imbalance of immune homeostasis in the GVHD process by transferring miR-16-5p. Our study provided further evidence that GVHD patients can benefit from hUCMSC-Exo-mediated therapy.

Discovery of Salifungin as a Repurposed Antibiotic against Methicillin-Resistant Staphylococcus aureus with Limited Resistance Development.

Exploring novel antimicrobial drugs and strategies has become essential to the fight MRSA-associated infections. Herein, we found that membrane-disrupted repurposed antibiotic salifungin had excellent bactericidal activity against MRSA, with limited development of drug resistance. Furthermore, adding salifungin effectively decreased the minimum inhibitory concentrations of clinical antibiotics against Staphylococcus aureus. Evaluations of the mechanism demonstrated that salifungin disrupted the level of H+ and K+ ions using hydrophilic and lipophilic groups to interact with bacterial membranes, causing the disruption of bacterial proton motive force followed by impacting on bacterial the function of the respiratory chain and adenosine 5'-triphosphate, thereby inhibiting phosphatidic acid biosynthesis. Moreover, salifungin also significantly inhibited the formation of bacterial biofilms and eliminated established bacterial biofilms by interfering with bacterial membrane potential and inhibiting biofilm-associated gene expression, which was even better than clinical antibiotics. Finally, salifungin exhibited efficacy comparable to or even better than that of vancomycin in the MRSA-infected animal models. In conclusion, these results indicate that salifungin can be a potential drug for treating MRSA-associated infections.

An early warning indicator of mortality risk in patients with COVID-19: the neutrophil extracellular traps/neutrophilic segmented granulocyte ratio.

Background: Neutrophil extracellular traps (NETs) play a key role in thrombus formation in patients with coronavirus disease 2019 (COVID-19). However, the existing detection and observation methods for NETs are limited in their ability to provide quantitative, convenient, and accurate descriptions of in situ NETs. Therefore, establishing a quantitative description of the relationship between NETs and thrombosis remains a challenge. Objective: We employed morphological observations of blood cells and statistical analyses to investigate the correlation between the NETs/neutrophilic segmented granulocyte ratio and mortality risk in patients with COVID-19. Methods: Peripheral blood samples were collected from 117 hospitalized patients with COVID-19 between November 2022 and February 2023, and various blood cell parameters were measured. Two types of smudge cells were observed in the blood and counted: lymphatic and neutral smudge cells. Statistical data analysis was used to establish COVID-19 mortality risk assessment indicators. Results: Morphological observations of neutrophilic smudge cells revealed swelling, eruption, and NETs formation in the neutrophil nuclei. Subsequently, the NETs/neutrophilic segmented granulocyte ratio (NNSR) was calculated. A high concentration of NETs poses a fatal risk for thrombus formation in patients. Statistical analysis indicated that a high NNSR was more suitable for evaluating the risk of death in patients with COVID-19 compared to elevated fibrinogen (FIB) and D-dimer (DD) levels. Conclusion: Observing blood cell morphology is an effective method for the detection of NETs, NNSR are important markers for revealing the mortality risk of patients with COVID-19.

Insights into the complementation potential of the extreme acidophile's orthologue in replacing Escherichia coli hfq gene-particularly in bacterial resistance to environmental stress.

Acidithiobacillus caldus is a typical extreme acidophile widely used in the biohydrometallurgical industry, which often experiences extreme environmental stress in its natural habitat. Hfq, an RNA-binding protein, typically functions as a global regulator involved in various cellular physiological processes. Yet, the biological functions of Hfq derived from such extreme acidophile have not been extensively investigated. In this study, the recombinant strain Δhfq/Achfq, constructed by CRISPR/Cas9-mediated chromosome integration, fully or partially restored the phenotypic defects caused by hfq deletion in Escherichia coli, including impaired growth performance, abnormal cell morphology, impaired swarming motility, decreased stress resistance, decreased intracellular ATP and free amino acid levels, and attenuated biofilm formation. Particularly noteworthy, the intracellular ATP level and biofilm production of the recombinant strain were increased by 12.2% and 7.0%, respectively, compared to the Δhfq mutant. Transcriptomic analysis revealed that even under heterologous expression, AcHfq exerted global regulatory effects on multiple cellular processes, including metabolism, environmental signal processing, and motility. Finally, we established a potential working model to illustrate the regulatory mechanism of AcHfq in bacterial resistance to environmental stress.

Enhancing column bioleaching of chalcocite by isolated iron metabolism partners Leptospirillum ferriphilum/Acidiphilium sp. coupling with systematically utilizing cellulosic waste.

The iron metabolism partners Leptospirillum ferriphilum and Acidiphilium sp. were screened from industrial bioheap site. An integrated multi-stage strategy was proposed to improve chalcolite column bioleaching coupling with synergistical utilization of cellulosic waste such as acid hydrolysate of aquatic plants. L. ferriphilum was used to accelerate the initial iron metabolism, and Acidithiobacillus caldus maintained a lower pH in the middle stage, while Acidiphilium sp. greatly inhibited jarosite passivation in the later stage. Meanwhile, L. ferriphilum (38.3 %) and Acidiphilium sp. (37.0 %) dominated the middle stage, while the abundance of Acidiphilium sp. reached 63.5 % in the later stage. The ferrous, sulfate ion and biomass were improved and the transcriptional levels of some biofilm and morphology related genes were significantly up-regulated. The final Cu2+ concentration reached 325.5 mg·L-1, improved by 43.8 %. Moreover, Canonical Correlation Analysis (CCA) analysis between bioleaching performance, iron/sulfur metabolism and community verified the important role of iron metabolism partners.

Impedance Iterative Learning Backstepping Control for Output-Constrained Multisection Continuum Arms Based on PMA.

BACKGROUND: Pneumatic muscle actuator (PMA) actuated multisection continuum arms are widely applied in various fields with high flexibility and bionic properties. Nonetheless, their kinematic modeling and control strategy proves to be extremely challenging tasks. METHODS: The relationship expression between the deformation parameters and the length of PMA with the geometric method is obtained under the assumption of piecewise constant curvature. Then, the kinematic model is established based on the improved D-H method. Considering the limitation of PMA telescopic length, an impedance iterative learning backstepping control strategy is investigated. For one thing, the impedance control is utilized to ensure that the ideal static balance force is maintained constant in the Cartesian space. For another, the iterative learning backstepping control is applied to guarantee that the desired trajectory of each PMA can be accurately tracked with the output-constrained requirement. Moreover, iterative learning control (ILC) is implemented to dynamically estimate the unknown model parameters and the precondition of zero initial error in ILC is released by the trajectory reconstruction. To further ensure the constraint requirement of the PMA tracking error, a log-type barrier Lyapunov function is employed in the backstepping control, whose convergence is demonstrated by the composite energy function. RESULTS: The tracking error of PMA converges to 0.004 m and does not exceed the time-varying constraint function through cosimulation. CONCLUSION: From the cosimulation results, the superiority and validity of the proposed theory are verified.

Comparison of the edible quality of liquid egg with different cooking methods and their antioxidant activity after in vitro digestion.

The purpose of this study was to compare the edible quality of liquid egg after steaming, baking, frying and microwaving. Texture profile analysis (TPA) and color analysis were used to evaluate the sensory characteristics of cooked eggs. The fat, vitamin A and E, protein and amino acid content of cooked eggs and the antioxidant activity after in vitro digestion were determined to display the variations in nutritional value. TPA results demonstrate that baked egg exhibited a softer and more elasticity texture, with a significant lower hardness of 3234 g than fried and microwaved eggs (p < 0.05). This is also consistent with the results of cohesiveness and chewiness. Consequences from scanning electron microscope showed plentiful honeycomb structure in baked egg, which may be related to the soft and elasticity texture. However, significantly higher contents of fat, vitamins A and E, protein were determined in fried egg (p < 0.05), which may be related to its lower moisture content. The strongest free radical scavenging efficiency for the hydroxyl, the DPPH and the superoxide radical were found in the gastrointestinal digestion of fried egg, with the rate of 95.76%, 81.08%, and 91.08%, respectively. Overall, baked egg showed superior soft and elasticity taste characteristics due to its honeycomb structure, while fried egg exhibited better antioxidant activity because of its high contents in vitamins and amino acids. The above results provide potential approach for the manufacture of pre-cooked eggs and related products using liquid eggs as ingredients.

Long-term treatment effect of a modified jailed-balloon technique for de Winter syndrome: a case report.

Timely recognition of the characteristic electrocardiographic pattern of de Winter syndrome is important for providing immediate reperfusion therapy for acute anterior myocardial infarction. In this case, an electrocardiogram showed 1- to 3-mm upsloping ST-segment depression at the J point in leads V1 to V6, with loss of R wave progression in leads V1 to V4. Urgent angiography showed occlusion of the proximal left anterior descending coronary artery and 70% stenosis in the ostial first diagonal branch (Medina type 1.1.1.). For this bifurcation lesion, we successfully performed a modified jailed-balloon technique to protect the side branch during percutaneous coronary intervention stenting. Thereafter, thrombolysis in myocardial infarction 3 flow was restored in both branches. This modified jailed-balloon technique is safe and effective in stent placement for de Winter syndrome without any loss of side branches.

The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury.

The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. It is unknown whether microsomal (m) prostaglandin (PG) E synthase (S)-1, a target downstream of COX, regulates myocardial (M) ischemia/reperfusion (I/R) injury, a key determinant of heart failure. Here we report that COX-1 and mPGES-1 mediate production of substantial amounts of PGE2 and confer cardiac protection in MI/R. Deletion of mPges-1 impairs cardiac microvascular perfusion and increases inflammatory cell infiltration in mouse MI/R. Consistently, mPges-1 deletion depresses the arteriolar dilatory response to I/R in vivo and to acetylcholine ex vivo, and enhances leukocyte-endothelial cell interaction, which is mediated via PGE receptor-4 (EP4). Furthermore, endothelium-restricted Ep4 deletion impairs microcirculation, and exacerbates MI/R injury, irrespective of EP4 agonism. Treatment with misoprostol, a clinically available PGE analogue, improves microcirculation and reduces MI/R injury. Thus, mPGES-1, a key microcirculation protector, constrains MI/R injury and this beneficial effect is partially mediated via endothelial EP4.

Loss of Endothelial CXCR7 Impairs Vascular Homeostasis and Cardiac Remodeling After Myocardial Infarction: Implications for Cardiovascular Drug Discovery.

BACKGROUND: Genome-wide association studies identified the association of the CXCL12 genetic locus (which encodes the chemokine CXCL12, also known as stromal cell-derived factor 1) with coronary artery disease and myocardial infarction (MI). Unlike CXCR4, the classic receptor for CXCL12, the function of CXCR7 (the most recently identified receptor) in vascular responses to injury and in MI remains unclear. METHODS: Tissue expression of CXCR7 was examined in arteries from mice and humans. Mice that harbored floxed CXCR7 and Cdh5-promoter driven CreERT2 were treated with tamoxifen to induce endothelium-restricted deletion of CXCR7. The resulting conditional knockout mice and littermate controls were studied for arterial response to angioplasty wire injury and cardiac response to coronary artery ligation. The role of CXCR7 in endothelial cell proliferation and angiogenesis was determined in vitro with cells from mice and humans. The effects of adenoviral delivery of CXCR7 gene and pharmacological activation of CXCR7 were evaluated in mice subjected to MI. RESULTS: Injured arteries from both humans and mice exhibited endothelial CXCR7 expression. Conditional endothelial CXCR7 deletion promoted neointimal formation without altering plasma lipid levels after endothelial injury and exacerbated heart functional impairment after MI, with increased both mortality and infarct sizes. Mechanistically, the exacerbated responses in vascular and cardiac remodeling are attributable to the key role of CXCR7 in promoting endothelial proliferation and angiogenesis. Impressively, the impaired post-MI cardiac remodeling occurred with elevated levels of CXCL12, which was previously thought to mediate cardiac protection by exclusively engaging its cognate receptor, CXCR4. In addition, both CXCR7 gene delivery via left ventricular injection and treatment with a CXCR7 agonist offered cardiac protection after MI. CONCLUSIONS: CXCR7 represents a novel regulator of vascular homeostasis that functions in the endothelial compartment with sufficient capacity to affect cardiac function and remodeling after MI. Activation of CXCR7 may have therapeutic potential for clinical restenosis after percutaneous coronary intervention and for heart remodeling after MI.

Experimental design-guided development of a stereospecific capillary electrophoresis assay for methionine sulfoxide reductase enzymes using a diastereomeric pentapeptide substrate.

A capillary electrophoresis method has been developed and validated to evaluate the stereospecific activity of recombinant human methionine sulfoxide reductase enzymes employing the C-terminally dinitrophenyl-labeled N-acetylated pentapeptide ac-KIFM(O)K-Dnp as substrate (M(O)=methionine sulfoxide). The separation of the ac-KIFM(O)K-Dnp diastereomers and the reduced peptide ac-KIFMK-Dnp was optimized using experimental design with regard to the buffer pH, buffer concentration, sulfated ß-cyclodextrin and 15-crown-5 concentration as well as capillary temperature and separation voltage. A fractional factorial response IV design was employed for the identification of the significant factors and a five-level circumscribed central composite design for the final method optimization. Resolution of the peptide diastereomers as well as analyte migration time served as responses in both designs. The resulting optimized conditions included 50mM Tris buffer, pH 7.85, containing 5mM 15-crown-5 and 14.3mg/mL sulfated ß-cyclodextrin, at an applied voltage of 25kV and a capillary temperature of 21.5°C. The assay was subsequently applied to the determination of the stereospecificity of recombinant human methionine sulfoxide reductases A and B2. The Michaelis-Menten kinetic data were determined. The pentapeptide proved to be a good substrate for both enzymes. Furthermore, the first separation of methionine sulfoxide peptide diastereomers is reported.