Human ST3Gal II and ST6GalNAc IV genes increase human serum-mediated cytotoxicity to xenogeneic cells.

Carbohydrate-antigens widely existed on glycoproteins and glycosphingolipids of all mammalian cells play a crucial role in self-defense and immunity. Xeno-reactive antibodies included in natural human sera play a protecting role in an acute phase-rejection of xenotransplantation. In this study, we investigated the effect of an alteration of glycosylation-pattern, caused by human sialyltransferases such as hST3Gal II or hST6GalNAc IV, on human serum mediated cytotoxicity in pig kidney PK15 cells. From LDH cytotoxicity assay, cytotoxicity to human serum was significantly increased in hST3Gal II and hST6GalNAc IV-transfected PK15 cells, as compared to the control. In the hST6Gal I-carrying cells, the cytotoxicity to human serum was rather decreased. Moreover, flow cytometry analysis revealed that an alteration of pig glycosylation-pattern by hST3Gal II or hST6GalNAc IV influences on a binding of human IgM or IgG, respectively, in pig kidney cells, regardless of Gal antigen alteration. Finally, we found that hST6GalNAc IV contributed to increase of terminal disialylated tetrasaccharide structure, disialyl T antigen, as evidenced by increase of the MAL II lectin binding capacity in the hST6GalNAc IV-transfected PK15 cells, compared with control. Therefore, our results suggest that carbohydrate antigens, such as disialyl T antigen, newly synthesized by the ST3Gal II- and ST6GalNAc IV are potentially believed to be new xeno-reactive elements.

Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.

Metabolism is an indispensable part of T cell proliferation, activation and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are composed of extracellular domains-often single-chain variable fragments (scFvs)-that determine ligand specificity and intracellular domains that trigger signalling following antigen binding. Here, we show that CARs differing only in the scFv variously reprogramme T cell metabolism. Even without exposure to antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observed basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harbouring a rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14G2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Modest overflow metabolism of CAR-T cells and metabolic compatibility between cancer cells and CAR-T cells are identified as features of efficacious CAR-T cell therapy.

Synergistic Effects in LaNiO3 Perovskites between Nickel and Iron Heterostructures for Improving Durability in Oxygen Evolution Reaction for AEMWE.

Perovskite materials that aren't stable during the oxygen evolution reaction (OER) are unsuitable for anion-exchange membrane water electrolyzers (AEMWE). But through manipulating their electronic structures, their performance can further increase. Among the first-row transition metals, nickel and iron are widely recognized as prominent electrocatalysts; thus, the researchers are looking into how combining them can improve the OER. Recent research has actively explored the design and study of heterostructures in this field, showcasing the dynamic exploration of innovative catalyst configurations. In this study, a heterostructure is used to manipulate the electronic structure of LaNiO3 (LNO) to improve both OER properties and durability. Through adsorbing iron onto the LNO (LNO@Fe) as γ iron oxyhydroxide (γ-FeOOH), the binding energy of nickel in the LNO exhibited negative shifts, inferring nickel movement toward the metallic state. Consequently, the electrochemical properties of LNO@Fe are further improved. LNO@Fe showed excellent performance (1.98 A cm-2, 1 m KOH, 50 °C at 1.85 V) with 84.1% cell efficiency in AEMWE single cells, demonstrating great improvement relative to LNO. The degradation for the 850 h durability analysis of LNO@Fe is ≈68 mV kh-1, which is ≈58 times less than that of LNO.

Comparative review of muscle fiber characteristics between porcine skeletal muscles.

Meat derived from skeletal muscles of animals is a highly nutritious type of food, and different meat types differ in nutritional, sensory, and quality properties. This study was conducted to compare the results of previous studies on the muscle fiber characteristics of major porcine skeletal muscles to the end of providing basic data for understanding differences in physicochemical and nutritional properties between different porcine muscle types (or meat cuts). Specifically, the muscle fiber characteristics between 19 major porcine skeletal muscles were compared. The muscle fibers that constitute porcine skeletal muscle can be classified into several types based on their contractile and metabolic characteristics. In addition, the muscle fiber characteristics, including size, composition, and density, of each muscle type were investigated and a technology based on these muscle fiber characteristics for improving meat quality or preventing quality deterioration was briefly discussed. This comparative review revealed that differences in muscle fiber characteristics are primarily responsible for the differences in quality between pork cuts (muscle types) and also suggested that data on muscle fiber characteristics can be used to develop optimal meat storage and packaging technologies for each meat cut (or muscle type).

Hydrophilic/Hydrophobic Janus Nanofibers Containing Compound K for Cartilage Regeneration.

Introduction: Cartilage regeneration is a challenging issue due to poor regenerative properties of tissues. Electrospun nanofibers hold enormous potentials for treatments of cartilage defects. However, nanofibrous materials used for the treatment of cartilage defects often require physical and/or chemical modifications to promote the adhesion, proliferation, and differentiation of cells. Thus, it is highly desirable to improve their surface properties with functionality. We aim to design hydrophilic, adhesive, and compound K-loaded nanofibers for treatments of cartilage defects. Methods: Hydrophilic and adhesive compound K-containing polycaprolactone nanofibers (CK/PCL NFs) were prepared by coatings of gallic acid-conjugated chitosan (CHI-GA). Therapeutic effects of CHI-GA/CK/PCL NFs were assessed by the expression level of genes involved in the cartilage matrix degradation, inflammatory response, and lipid accumulations in the chondrocytes. In addition, Cartilage damage was evaluated by safranin O staining and immunohistochemistry of interleukin-1ß (IL-1ß) using OA animal models. To explore the pathway associated with therapeutic effects of CHI-GA/CK/PCL NFs, cell adhesion, phalloidin staining, and the expression level of integrins and peroxisome proliferator-activated receptor (PPARs) were evaluated. Results: CHI-GA-coated side of the PCL NFs showed hydrophilic and adhesive properties, whereas the unmodified opposite side remained hydrophobic. The expression levels of genes involved in the degradation of the cartilage matrix, inflammation, and lipogenesis were decreased in CHI-GA/CK/PCL NFs owing to the release of CK. In vivo implantation of CHI-GA/CK/PCL NFs into the cartilage reduced cartilage degradation induced by destabilization of the medial meniscus (DMM) surgery. Furthermore, the accumulation of lipid deposition and expression levels of IL-1ß was reduced through the upregulation of PPAR. Conclusion: CHI-GA/CK/PCL NFs were effective in the treatments of cartilage defects by inhibiting the expression levels of genes involved in cartilage degradation, inflammation, and lipogenesis as well as reducing lipid accumulation and the expression level of IL-1ß via increasing PPAR.

Hollow Microcavity Electrode for Enhancing Light Extraction.

Luminous efficiency is a pivotal factor for assessing the performance of optoelectronic devices, wherein light loss caused by diverse factors is harvested and converted into the radiative mode. In this study, we demonstrate a nanoscale vacuum photonic crystal layer (nVPCL) for light extraction enhancement. A corrugated semi-transparent electrode incorporating a periodic hollow-structure array was designed through a simulation that utilizes finite-difference time-domain computational analysis. The corrugated profile, stemming from the periodic hollow structure, was fabricated using laser interference lithography, which allows the precise engineering of various geometrical parameters by controlling the process conditions. The semi-transparent electrode consisted of a 15 nm thick Ag film, which acted as the exit mirror and induced microcavity resonance. When applied to a conventional green organic light-emitting diode (OLED) structure, the optimized nVPCL-integrated device demonstrated a 21.5% enhancement in external quantum efficiency compared to the reference device. Further, the full width at half maximum exhibited a 27.5% reduction compared to that of the reference device, demonstrating improved color purity. This study presents a novel approach by applying a hybrid thin film electrode design to optoelectronic devices to enhance optical efficiency and color purity.

What do we know about dermal bioaccessibility of metals coated on antibacterial films?

Antibacterial films have gained attention since the outbreak of the COVID-19 pandemic; however, the impact of metals contained in antibacterial films on human safety have not been sufficiently investigated. This study reports on the important features that must be considered when assessing the bioaccessibility of Ag, Cu, and Zn in antibacterial films. Specifically, the effects of the artificial sweat component (i.e., amino acid and pH), surface weathering of antibacterial films, wipe sampling, and sebum were carefully examined. Our findings suggest that amino acids greatly affect bioaccessibility as amino acids act as ligands to facilitate metal ion leaching. In addition, constant exposure to ultraviolet C causes the film surface to oxidize, which significantly increases metal bioaccessibility due to the electrostatic repulsion between metal oxides and organic substrates. The presence of sebum in artificial sweat and physical damage to the film surface had no significant effects. Furthermore, the wipe sampling used to mimic the realistic dermal contact suggests the feasibility of applying this method for the assessment of bioaccessibility of metals in antibacterial films. The method offers significant advantages for evaluating the human safety aspects of skin contact with consumer products in future research.

Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

A novel Mycobacterium Tuberculosis antigen, MTB48 enhances inflammatory response in LPS-induced RAW264.7 macrophage immune cells.

Mtb (Mycobacterium tuberculosis) is a pathogenic bacterium that causes tuberculosis infection (TB). Mtb-secreted proteins have recently been investigated as virulence factors, as well as therapeutic and vaccine possibilities. The early-secreted antigen target MTB48 is one of these proteins that has been explored as a cocktail antigen in the serodiagnosis of active tuberculosis. However, there exists no information about the function or control of MTB48's inflammatory activity in macrophages at the site of inflammation. As a result, the goal of this research was to figure out what processes are involved in MTB48's function. MTB48 stimulated inflammation in LPS induced macrophages at both the protein and mRNA levels, which was interesting. MTB48 aided LPS induced IB phosphorylation and NF-κB translocation. MTB48 also led to the phosphorylation of MAPK signaling protein. These findings imply that MTB48 can enhance inflammatory activity via NF-κB and MAPK signaling by upregulating COX-2, iNOS, NO and PGE2. Many tuberculosis antigens have been tested for the development of rapid serological diagnosis. The results of this study suggest that MTB48 is a very high conservative antigen and is a major factor causing inflammatory reactions, suggesting that it can help control and diagnose tuberculosis.

A parallel glycolysis provides a selective advantage through rapid growth acceleration.

Glycolysis is a universal metabolic process that breaks down glucose to produce adenosine triphosphate (ATP) and biomass precursors. The Entner-Doudoroff (ED) pathway is a glycolytic pathway that parallels textbook glycolysis but yields half as much ATP. Accordingly, in organisms that possess both glycolytic pathways (for example, Escherichia coli), its raison d'être remains a mystery. In this study, we found that the ED pathway provides a selective advantage during growth acceleration. Upon carbon and nitrogen upshifts, E. coli accelerates growth faster with than without the ED pathway. Concurrent isotope tracing reveals that the ED pathway flux increases faster than that of textbook glycolysis. We attribute the fast response time of the ED pathway to its strong thermodynamic driving force and streamlining of glucose import. Intermittent nutrient supply manifests the evolutionary advantage of the parallel glycolysis; thus, the dynamic nature of an ostensibly redundant pathway's role in promoting rapid adaptation constitutes a metabolic design principle.

Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.

Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.

Inflammation-Targeting Mesenchymal Stem Cells Combined with Photothermal Treatment Attenuate Severe Joint Inflammation.

Current clinical therapeutic efficacy for the treatment of osteo- and rheumatoid-arthritis is obviously limited. Although mesenchymal stem cells (MSCs) are considered as a source of promising regenerative therapy, un-modified or genetically engineered MSCs injected in vivo restrict their clinical utility because of the low drug efficacy and unpredicted side effect, respectively. Herein, a strategy to enhance the migration efficacy of MSCs to inflamed joints via an inflammation-mediated education process is demonstrated. To reinforce the limited anti-inflammatory activity of MSCs, gold nanostar loaded with triamcinolone is conjugated to MSC. Furthermore, near-infrared laser-assisted photothermal therapy (PTT) induced by gold nanostar significantly elevates the anti-inflammatory efficacy of the developed drugs, even in advanced stage arthritis model. An immunological regulation mechanism study of PTT is first suggested in this study; the expression of the interleukin 22 receptor, implicated in the pathogenesis of arthritis, is downregulated in T lymphocytes by PTT, and Th17 differentiation from naïve CD4 T cell is inhibited. Collectively, inflammation-targeting MSCs conjugated with triamcinolone-loaded gold nanostar (Edu-MSCs-AuS-TA) promote the repolarization of macrophages and decrease neutrophil recruitment in joints. In addition, Edu-MSCs-AuS-TA significantly alleviate arthritis-associated pain, improve general locomotor activity, and more importantly, induce cartilage regeneration even for severe stages of arthritis model.

Determination of Metabolic Fluxes by Deep Learning of Isotope Labeling Patterns.

Fluxomics offers a direct readout of metabolic state but relies on indirect measurement. Stable isotope tracers imprint flux-dependent isotope labeling patterns on metabolites we measure; however, the relationship between labeling patterns and fluxes remains elusive. Here we innovate a two-stage machine learning framework termed ML-Flux that streamlines metabolic flux quantitation from isotope tracing. We train machine learning models by simulating atom transitions across five universal metabolic models starting from 26 13C-glucose, 2H-glucose, and 13C-glutamine tracers within feasible flux space. ML-Flux employs deep-learning-based imputation to take variable measurements of labeling patterns as input and successive neural networks to convert the ensuing comprehensive labeling information into metabolic fluxes. Using ML-Flux with multi-isotope tracing, we obtain fluxes through central carbon metabolism that are comparable to those from a least-squares method but orders-of-magnitude faster. ML-Flux is deployed as a webtool to expand the accessibility of metabolic flux quantitation and afford actionable information on metabolism.

Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer.

Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing's syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing's syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.

Remimazolam sedation with regional anesthesia in difficult airway due to huge thyroid goiter: A case report.

RATIONALE: Remimazolam, a novel benzodiazepine, is known to have less respiratory depression compared to other anesthetic agents, and it also has a reversal agent that can be used in emergency situations. Remimazolam with these characteristics can be usefully utilized in the anesthetic management of patients with difficult airway. PATIENT CONCERNS: A 78-year-old female patient was scheduled proximal humerus fracture surgery. The patient occasionally complained dyspnea and had multiple comorbidities including thyroid goiter, dementia, and delirium. DIAGNOSES: The patient had a large thyroid goiter compressing and deviating the trachea. A short neck with increased circumference was confirmed. A difficult airway was anticipated in the preanesthetic evaluation. INTERVENTIONS: Sedation with remimazolam followed by regional anesthesia was performed for the surgery. OUTCOMES: The surgery was completed without complications. The patient recovered and was discharged on 15th postoperative days. LESSONS: The use of remimazolam for sedation may be an appropriate option in the anesthetic management of patients with difficult airway.

Comparative analysis of the capability of the extended biotic ligand model and machine learning approaches to predict arsenate toxicity.

Assessment of inorganic arsenate (As(V)) is critical for ensuring a sustainable environment because of its adverse effects on humans and ecosystems. This study is the first to attempt to predict As(V) toxicity to the bioluminescent bacterium Aliivibrio fischeri exposed to varying As(V) dosages and environmental factors (pH and phosphate concentration) using six machine learning (ML)-guided models. The predicted toxicity values were compared with those predicted using the extended biotic ligand model (BLM) we previously developed to evaluate the toxic effect of oxyanion (i.e., As(V)). The relationship between the variables (input features) and toxicity (output) was found to play an important role in the prediction accuracy of each ML-guided model. The results indicated that the extended BLM had the highest prediction accuracy, with a root mean square error (RMSE) of 12.997. However, with an RMSE of 14.361, the multilayer perceptron (MLP) model exhibited quasi-accurate prediction, despite having been trained with a relatively small dataset (n = 256). In view of simplicity, an MLP model is compatible with an extended BLM and does not require expert knowledge for the derivation of specific parameters, such as binding fraction and binding constant values. Furthermore, with the development and employment of reliable in-situ sensing techniques, monitoring data are expected to be augmented faster to provide sufficient training data for the improvement of prediction accuracy which may, thus, allow it to outperform the extended BLM after obtaining sufficient data.

GM1a ganglioside-binding domain peptide inhibits host adhesion and inflammatory response of enterotoxigenic Escherichia coli heat-labile enterotoxin-B in HCT-8 cells.

Enterotoxigenic Escherichia coli (ETEC) is a major cause of illness and death but has no effective therapy. The heat-labile enterotoxin LT is a significant virulence factor produced by ETEC. The heat-labile enterotoxin-B (LT-B) subunit may enter host cells by binding to monosialotetrahexosylganglioside-a (GM1a), a monosialoganglioside found on the plasma membrane surface of animal epithelial cells. This research was conducted to develop conformationally comparable peptides to the carbohydrate epitope of GM1a for the treatment of ETEC. We used the LT-B subunit to select LT-B-binding peptides that structurally resemble GM1a. The ganglioside microarray and docking simulations were used to identify three GM1a ganglioside-binding domain (GBD) peptides based on LT-B recognition. Peptides had an inhibiting effect on the binding of LT-B to GM1a. The binding capacity, functional inhibitory activity, and in vitro effects of the GBD peptides were evaluated using HCT-8 cells, a human intestinal epithelial cell line, to evaluate the feasibility of deploying GBD peptides to combat bacterial infections. KILSYTESMAGKREMVIIT was the most efficient peptide in inhibiting cellular absorption of LT-B in cells. Our findings offer compelling evidence that GM1a GBD-like peptides might act as new therapeutics to inhibit LT-B binding to epithelial cells and avoid the subsequent physiological consequences of LT.

Unexpected metabolic rewiring of CO2 fixation in H2-mediated materials-biology hybrids.

A hybrid approach combining water-splitting electrochemistry and H2-oxidizing, CO2-fixing microorganisms offers a viable solution for producing value-added chemicals from sunlight, water, and air. The classic wisdom without thorough examination to date assumes that the electrochemistry in such a H2-mediated process is innocent of altering microbial behavior. Here, we report unexpected metabolic rewiring induced by water-splitting electrochemistry in H2-oxidizing acetogenic bacterium Sporomusa ovata that challenges such a classic view. We found that the planktonic S. ovata is more efficient in utilizing reducing equivalent for ATP generation in the materials-biology hybrids than cells grown with H2 supply, supported by our metabolomic and proteomic studies. The efficiency of utilizing reducing equivalents and fixing CO2 into acetate has increased from less than 80% of chemoautotrophy to more than 95% under electroautotrophic conditions. These observations unravel previously underappreciated materials' impact on microbial metabolism in seemingly simply H2-mediated charge transfer between biotic and abiotic components. Such a deeper understanding of the materials-biology interface will foster advanced design of hybrid systems for sustainable chemical transformation.