GSNOR overexpression enhances CAR-T cell stemness and anti-tumor function by enforcing mitochondrial fitness.

Chimeric antigen receptor-T (CAR-T) cell has been developed as a promising agent for patients with refractory or relapsed lymphoma and leukemia, but not all the recipients could achieve a long-lasting remission. The limited capacity of in vivo expansion and memory differentiation post activation is one of the major reasons for suboptimal CAR-T therapeutic efficiency. Nitric oxide (NO) plays multifaceted roles in mitochondrial dynamics and T cell activation, but its function on CAR-T cell persistence and anti-tumor efficacy remains unknown. Herein, we found the continuous signaling from CAR not only promotes excessive NO production, but also suppressed S-nitrosoglutathione reductase (GSNOR) expression in T cells, which collectively led to increased protein S-nitrosylation, resulting in impaired mitochondrial fitness and deficiency of T cell stemness. Intriguingly, enforced expression of GSNOR promoted memory differentiation of CAR-T cell after immune activation, rendered CAR-T better resistance to mitochondrial dysfunction, further enhanced CAR-T cell expansion and anti-tumor capacity in vitro and in a mouse tumor model. Thus, we revealed a critical role of NO in restricting CAR-T cell persistence and functionality, and defined that GSNOR overexpression may provide a solution to combat NO stress and render patients with more durable protection from CAR-T therapy.

Loss of Lkb1 in CD11c+ myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance.

Adipose tissue CD11c+ myeloid cell is an independent risk factor associated with obesity and metabolic disorders. However, the underlying molecular basis remains elusive. Here, we demonstrated that liver kinase B1 (Lkb1), a key bioenergetic sensor, is involved in CD11c+ cell-mediated immune responses in diet-induced obesity. Loss of Lkb1 in CD11c+ cells results in obesity resistance but lower glucose tolerance, which accompanies tissue-specific immune abnormalities. The accumulation and CD80's expression of Lkb1 deficient adipose-tissue specific dendritic cells but not macrophages is restrained. Additionally, the balance of IL-17A and IFN-γ remarkably tips towards the latter in fat T cells and CD11c- macrophages. Mechanistically, IFN-γ promotes apoptosis of preadipocytes and inhibits their adipogenesis while IL-17A promotes the adipogenesis in vitro, which might account in part for the fat gain resistant phenotype. In summary, these findings reveal that Lkb1 is essential for fat CD11c+ dendritic cells responding to HFD exposure and provides new insights into the IL-17A/IFN-γ balance in HFD-induced obesity.

Bifidobacterium spp. as functional foods: A review of current status, challenges, and strategies.

Members of Bifidobacterium are among the first microbes to colonize the human intestine naturally, their abundance and diversity in the colon are closely related to host health. Recently, the gut microbiota has been gradually proven to be crucial mediators of various metabolic processes between the external environment and the host. Therefore, the health-promoting benefits of Bifidobacterium spp. and their applications in food have gradually been widely concerned. The main purpose of this review is to comprehensively introduce general features, colonization methods, and safety of Bifidobacterium spp. in the human gut, highlighting its health benefits and industrial applications. On this basis, the existing limitations and scope for future research are also discussed. Bifidobacteria have beneficial effects on the host's digestive system, immune system, and nervous system. However, the first prerequisite for functioning is to have enough live bacteria before consumption and successfully colonize the colon after ingestion. At present, strain breeding, optimization (e.g., selecting acid and bile resistant strains, adaptive evolution, high cell density culture), and external protection technology (e.g., microencapsulation and protectants) are the main strategies to address these challenges in food application.

Deciphering the Heterogeneity of Mitochondrial Functions During Hematopoietic Lineage Differentiation.

BACKGROUND: The heterogeneity of mitochondrial function is an important feature of hematopoietic cell lineage differentiation, but its stage wise contribution is not adequately studied. To establish a model to compare the lineage differentiation of hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and differentiated blood cells, the mitochondrial mass (MM), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitophagy level were analyzed. RESULTS AND DISCUSSION: HSCs had lower mitochondrial metabolic activity than committed progenitor populations, indicated by lower MM, MMP, and ROS and higher mitophagy. HPC1s shared more stem cell characteristics than HPC2s and committed progenitor populations in terms of mitochondrial number and function. The mitochondrial metabolism of mature blood cells had greater heterogeneity than hematopoietic stem and progenitor cells, with granulocytes being similar to monocytes. Moreover, HSCs exhibited heterogeneity in the selection of mitophagy-related PINK1/PARK2, BNIP3/NIX, and FUNDC1 pathways. Myeloid differentiation had greater morphological and functional heterogeneity of hematopoietic cells than lymphoid differentiation. Additionally, leukemia stem cells had higher aerobic metabolism and better stem cell function through elevated mitophagy than normal hematopoietic cells. ROS and MMP levels in differentiated leukemia cells were higher, but the level of mitophagy was lower than in differentiated hematopoietic cells. CONCLUSION: This study provides a complete set of methods and basic reference values for the systematic study of the mitochondrial metabolic function of different types of hematopoietic cells under physiological and pathological conditions. The findings contribute to the future research of tumor and aging based on mitochondrial metabolism.

Structural characterization and immunological activity of pectin polysaccharide from kiwano (Cucumis metuliferus) peels.

Two novel polysaccharides, namely CMPP-1 and CMPP-2, from kiwano (Cucumis metuliferus) peels were isolated through hot-water extraction, followed by ethanol precipitation and column chromatography. The results showed that CMPP-1 and CMPP-2 were hetero-galacturonans with different molecular weights of 7.35 kDa and 6.90 kDa, respectively. Both of CMPP-1 and CMPP-2 were mainly composed of glucuronic acid (45.93 % and 51.75 %, respectively), and other monosaccharides including rhamnose, arabinose, galactose, glucose, xylose, fucose, mannose, galacturonic acid, and mannuronic acid. The results of structural characterization from FT-IR and NMR confirmed that CMPP-1 and CMPP-2 were pectin with highly branched structure. Furthermore, both CMPP-1 and CMPP-2 possessed immune-enhancing activity and could enhance the secretion of nitric oxide and cytokines (TNF-α, IL-6) in a dose-dependent manner. Especially, CMPP-1 had higher immune activity than CMPP-2 as the minimum effective concentration were 0.78 µg/mL and 6.25 µg/mL, respectively. These findings provide a scientific basis for further utilization of polysaccharide from kiwano peels.

The Analysis of How Apnea Influences the Autonomic Nervous System Using Short-Term Heart Rate Variability Indices.

Objective: Frequent cessations of respiration can greatly increase the prevalence rate of arrhythmia. It has been confirmed that cardiac modulation is regulated by the autonomic nervous system (ANS). And heart rate variability (HRV) is widely used as a method to evaluate the function of the ANS. Therefore, we analyzed whether apnea can affect the balance and normal function of the ANS using short-term HRV indices. Methods: Forty-five healthy subjects were asked to breathe normally and hold their breathing to simulate 10 times apnea. Thirty-six patients from the dataset of a sleep laboratory for the diagnosis of sleep disorders with 10 times apnea were included in analysis. We calculated short-term HRV indices of subjects in normal respiratory and apneic states, respectively. Results: Compared with the normal respiratory state, respiration cease would lead to the values of Mean-RR, nLF, LF/HF, and α1 which significantly increased, whereas the values of rMSSD and nHF significantly decreased. Conclusions: Cessations of respiration would lead to an imbalance in the function of the ANS, as well as an increase in fractal characteristics of the heart. These changes in the physiological state are likely to induce and cause the occurrence of arrhythmia, which is regulated by the ANS.

Structural Analysis and Antioxidant Activity of Extracellular Polysaccharides Extracted from Culinary-Medicinal White Jelly Mushroom Tremella fuciformis (Tremellomycetes) Conidium Cells.

Using Tremella fuciformis conidium cells for submerged fermentation is a cost-effective way to harvest bioactive compounds. In this study, we emphasized the structural and functional analysis of extracellular polysaccharides (EPS) extracted from T. fuciformis conidium cells. An EPS high-yield strain tyc63 was selected and a 6-day optimum fermentation period was determined. Crude EPS was extracted and three high molecular weight (5189, 171.6, and 661 kDa) polysaccharides TFP-1, TFP-2, and TFP-3 were isolated and purified. TFP-1 is mainly composed of glucose, xylose, mannose, and fucose, while both TFP-2 and TFP-3 are mainly composed of rhamnose, arabinose, mannose, galactose, and glucose. FT-IR analysis revealed that TFP-1, TFP-2, and TFP-3 have typical polysaccharide structure. The antioxidant assay revealed that the crude EPS, TFP-1, TFP-2, and TFP-3 presented high free radical scavenging activities but low ferric reducing power, suggesting that the EPS produced by liquid fermentation could be used as a potent radical scavenger.

Adaptive Filtering Improved Apnea Detection Performance Using Tracheal Sounds in Noisy Environment: A Simulation Study.

OBJECTIVE: Tracheal sounds were used to detect apnea on various occasions. However, ambient noises can contaminate tracheal sounds which result in poor performance of apnea detection. The objective of this paper was to apply the adaptive filtering (AF) algorithm to improve the quality of tracheal sounds and examine the accuracy of the apnea detection algorithm using tracheal sounds after AF. METHOD: Tracheal sounds were acquired using a primary microphone encased in a plastic bell, and the ambient noises were collected using a reference microphone resting outside the plastic bell in quiet and noisy environments, respectively. Simultaneously, the flow pressure signals and thoracic and abdominal movement were obtained as the standard signals to determine apnea events. Then, the normalized least mean square (NLMS) AF algorithm was applied to the tracheal sounds mixed with noises. Finally, the algorithm of apnea detection was used to the tracheal sounds with AF and the tracheal sounds without AF. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and Cohen's kappa coefficient of apnea detection were calculated. RESULTS: Forty-six healthy subjects, aged 18-35 years and with BMI < 21.4, were included in the study. The apnea detection performance using tracheal sounds was as follows: in the quiet environment, the tracheal sounds without AF detected apnea with 97.2% sensitivity, 99.9% specificity, 99.8% PPV, 99.4% NPV, 99.5% accuracy, and 0.982 kappa coefficient. The tracheal sounds with AF detected apnea with 98.2% sensitivity, 99.9% specificity, 99.4% PPV, 99.6% NPV, 99.6% accuracy, and 0.985 kappa coefficient. While in the noisy environment, the tracheal sounds without AF detected apnea with 81.1% sensitivity, 96.9% specificity, 85.1% PPV, 96% NPV, 94.2% accuracy, and 0.795 kappa coefficient and the tracheal sounds with AF detected apnea with 91.5% sensitivity, 97.4% specificity, 88.4% PPV, 98.2% NPV, 96.4% accuracy, and 0.877 kappa coefficient. CONCLUSION: The performance of apnea detection using tracheal sounds with the NLMS AF algorithm in the noisy environment proved to be accurate and reliable. The AF technology could be applied to the respiratory monitoring using tracheal sounds.

Structural characterization and immune-enhancing activity of a novel high-molecular-weight polysaccharide from Cordyceps militaris.

A novel homogeneous polysaccharide (CMP-III) was extracted and purified from C. militaris. Structural characterization revealed that CMP-III had an average molecular weight of 4.796 × 104 kDa and consisted of glucose, mannose and galactose with the molar ratio of 8.09:1.00:0.25. The main linkage types of CMP-III consisted of 1 â†’ 4)-α-D-Glc (70.08%), 1 â†’ 4,6)-α-D-Man (9.59%), 1→)-α-D-Man (10.79%) and 1 → 2,6)-α-D-Gal (3.93%) based on methylation and NMR analysis. The immunomodulatory assay indicated that CMP-III significantly promoted macrophage phagocytosis and secretion of NO, TNF-α and IL-6. Further study suggested that macrophage activated by CMP-III involved mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-B (NF-κB) signaling pathways. Overall, these results suggested that CMP-III could be developed as a potent immunomodulatory agent for use in functional foods and dietary supplements.

[Impacts of climate change on food production in Gansu: A review].

The climate of Gansu turned to be overall warming-drying and partly warming-wetting since 1986. In contrast to that of 1960, the average annual temperature had raised by 1.1°C with the average annual precipitation decreased by 28 mm correspondingly, which made the arid region expanded southward by 50 km in 2010. Climate warming increased the growth period effective accumulated temperature of main food grain crops and lengthened the crop growth period. It changed crop maturity, crop disposition, cropping system and generally increased the cultivatable area and planting altitude above the sea level of major crops and expanded northward the multiple cropping system, which further resulted in expansion of autumn grain crop sown area, shrink of summer grain crop sown area, and replacement of strong winter early maturing varieties by weak winter middle late maturing varieties. It benefited the crop yield by increasing the use efficiency of photo-thermal resources. Warming-wetting climate increased the climate productivity of oasis crop while warming-drying weather decreased the climate productivity of rainfed crops, which were mostly determined by the precipitation regimes and water conditions. Any advanced technique that can increase precipitation use ratio and water use efficiency as well as improve and promote soil quality and fertility should be regarded as an effective countermeasure to increase food grain production under climate change in Gsansu. So, selecting and breeding new crop varieties with the characteristics of strong resistance, weak winter, middle-late mature and high water use efficiency, establishing new planting structure and cropping system that suitable to the precipitation and temperature features of changed climate, are the development direction of food grain production in Gansu to cope with the climate change.

Size control synthesis of polymer-stabilized water-soluble platinum oxide nanoparticles.

A series of narrowly distributed nanoparticles with different sizes of platinum oxide stabilized by polyvinylpyrrolidone (PVP) were synthesized by hydrolytic decomposition of platinum chloride. The as-synthesized nanoparticles were characterized by UV-vis, TEM, and XPS examination. Studies on the parameters influencing the size of the as-synthesized platinum oxide nanoparticles were carried out. The pH of the solution was demonstrated to be the main factor affecting the particle diameter. The particles size also decreased with the increasing molar ratio of stabilizer (PVP):PtCl(4). The influence of the concentration of sodium acetate on the rate of hydrolytic decomposition and the condensation reaction was studied. It was found that increasing the concentration of sodium acetate increased the rate of the condensation reaction nearly linearly.

Synthesis of solvent-stabilized colloidal nanoparticles of platinum, rhodium, and ruthenium by microwave-polyol process.

Solvent-stabilized Pt, Rh, and Ru colloidal nanoparticles were synthesized by a microwave-polyol process. They were characterized by TEM and XPS, XRD, and UV-vis examination. These colloids have small particle sizes with narrow size distribution, and they were stable in glycol upon storage under ambient condition for months. Separation and XPS characterization of the intermediate colloids demonstrated the two-step mechanism for the formation of solvent-stabilized metal colloids via hydrolysis.

Unexpected effects of trace impurities on the properties of polymer-stabilized ruthenium colloids from different sources of ruthenium(III) chloride hydrate.

The stability and the catalytic performances of polyvinylpyrrolidone-stabilized ruthenium colloids (PVP-Ru) prepared by using RuCl(3).xH(2)O of different sources have been investigated. The trace impurity content of platinum and palladium in RuCl(3).xH(2)O was demonstrated to be the main factors affecting the properties of PVP-Ru colloids.