α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development.

The rapid proliferation of cancer cells and dysregulated vasculature within the tumor leads to limited nutrient accessibility. Cancer cells often rewire their metabolic pathways for adaption to nutrient stress, and the underlying mechanism remains largely unknown. Glutamate dehydrogenase 1 (GDH1) is a key enzyme in glutaminolysis that converts glutamate to α-ketoglutarate (α-KG). Here, we show that, under low glucose, GDH1 is phosphorylated at serine (S) 384 and interacts with RelA and IKKß. GDH1-produced α-KG directly binds to and activates IKKß and nuclear factor κB (NF-κB) signaling, which promotes glucose uptake and tumor cell survival by upregulating GLUT1, thereby accelerating gliomagenesis. In addition, GDH1 S384 phosphorylation correlates with the malignancy and prognosis of human glioblastoma. Our finding reveals a unique role of α-KG to directly regulate signal pathway, uncovers a distinct mechanism of metabolite-mediated NF-κB activation, and also establishes the critical role of α-KG-activated NF-κB in brain tumor development.

Macrophage-Associated PGK1 Phosphorylation Promotes Aerobic Glycolysis and Tumorigenesis.

Macrophages are a dominant leukocyte population in the tumor microenvironment and actively promote cancer progression. However, the molecular mechanism underlying the role of macrophages remains poorly understood. Here we show that polarized M2 macrophages enhance 3-phosphoinositide-dependent protein kinase 1 (PDPK1)-mediated phosphoglycerate kinase 1 (PGK1) threonine (T) 243 phosphorylation in tumor cells by secreting interleukin-6 (IL-6). This phosphorylation facilitates a PGK1-catalyzed reaction toward glycolysis by altering substrate affinity. Inhibition of PGK1 T243 phosphorylation or PDPK1 in tumor cells or neutralization of macrophage-derived IL-6 abrogates macrophage-promoted glycolysis, proliferation, and tumorigenesis. In addition, PGK1 T243 phosphorylation correlates with PDPK1 activation, IL-6 expression, and macrophage infiltration in human glioblastoma multiforme (GBM). Moreover, PGK1 T243 phosphorylation also correlates with malignance and prognosis of human GBM. Our findings demonstrate a novel mechanism of macrophage-promoted tumor growth by regulating tumor cell metabolism, implicating the therapeutic potential to disrupt the connection between macrophages and tumor cells by inhibiting PGK1 phosphorylation.

UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis.

Cancer metastasis is the primary cause of morbidity and mortality, and accounts for up to 95% of cancer-related deaths1. Cancer cells often reprogram their metabolism to efficiently support cell proliferation and survival2,3. However, whether and how those metabolic alterations contribute to the migration of tumour cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid4. Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine 473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R (HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL initiates the epithelial-mesenchymal transition, thus promoting the migration of tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour metastasis by increasing the stability of SNAI1 mRNA.

Mn─O Covalency as a Lever for Na⁺ Intercalation Kinetics: The Role of Oxygen Edge-Sharing Co Octahedral Sites in MnO2.

The strategic enhancement of manganese-oxygen (Mn─O) covalency is a promising approach to improve the intercalation kinetics of sodium ions (Na⁺) in manganese dioxide (MnO2). In this study, an augmenting Mn─O covalency in MnO2 by strategically incorporating cobalt at oxygen edge-sharing Co octahedral sites is focused on. Both experimental results and density functional theory (DFT) calculations reveal an increased electron polarization from oxygen to manganese, surpassing that directed toward cobalt, thereby facilitating enhanced electron transfer and strengthening covalency. The synthesized Co-MnO2 material exhibits outstanding electrochemical performance, demonstrating a superior specific capacitance of 388 F g-1 at 1 A g-1 and maintaining 97.21% capacity retention after 12000 cycles. Additionally, an asymmetric supercapacitor constructed using Co-MnO2 achieved a high energy density of 35 Wh kg-1 at a power density of 1000 W kg-1, underscoring the efficacy of this material in practical applications. This work highlights the critical role of transition metal-oxygen interactions in optimizing electrode materials and introduces a robust approach to enhance the functional properties of manganese oxides, thereby advancing high-performance energy storage technologies.

Quantum Spin Exchange Interactions Trigger O†p Band Broadening for Enhanced Aqueous Zinc-Ion Battery Performance.

The pressing demand for large-scale energy storage solutions has propelled the development of advanced battery technologies, among which zinc-ion batteries (ZIBs) are prominent due to their resource abundance, high capacity, and safety in aqueous environments. However, the use of manganese oxide cathodes in ZIBs is challenged by their poor electrical conductivity and structural stability, stemming from the intrinsic properties of MnO2 and the destabilizing effects of ion intercalation. To overcome these limitations, our research delves into atomic-level engineering, emphasizing quantum spin exchange interactions (QSEI). These essential for modifying electronic characteristics, can significantly influence material efficiency and functionality. We demonstrate through density functional theory (DFT) calculations that enhanced QSEI in manganese oxides broadens the O p band, narrows the band gap, and optimizes both proton adsorption and electron transport. Empirical evidence is provided through the synthesis of Ru-MnO2 nanosheets, which display a marked increase in energy storage capacity, achieving 314.4 mAh g-1 at 0.2 A g-1 and maintaining high capacity after 2000 cycles. Our findings underscore the potential of QSEI to enhance the performance of TMO cathodes in ZIBs, pointing to new avenues for advancing battery technology.

Spin Symmetry Breaking-Induced Hubbard Gap Near-Closure in N-Coordinated MnO2 for Enhanced Aqueous Zinc-Ion Battery Performance.

Transition metal oxides (TMOs) are promising cathode materials for aqueous zinc ion batteries (ZIBs), however, their performance is hindered by a substantial Hubbard gap, which limits electron transfer and battery cyclability. Addressing this, we introduce a heteroatom coordination approach, using triethanolamine to induce axial N coordination on Mn centers in MnO2, yielding N-coordinated MnO2 (TEAMO). This approach leverages the change of electronegativity disparity between Mn and ligands (O and N) to disrupt spin symmetry and augment spin polarization. This enhancement leads to the closure of the Hubbard gap, primarily driven by the intensified occupancy of the Mn eg orbitals. The resultant TEAMO exhibit a significant increase in storage capacity, reaching 351 mAh g-1 at 0.1 A g-1. Our findings suggest a viable strategy for optimizing the electronic structure of TMO cathodes, enhancing the potential of ZIBs in energy storage technology.

Quantitative Proteomics Reveal the Role of Matrine in Regulating Lipid Metabolism.

Hyperlipidemia (HLP) is a prevalent systemic metabolic disorder characterized by disrupted lipid metabolism. Statin drugs have long been the primary choice for managing lipid levels, but intolerance issues have prompted the search for alternative treatments. Matrine, a compound derived from the traditional Chinese medicine Kushen, exhibits anti-inflammatory and lipid-lowering properties. Nevertheless, the mechanism by which matrine modulates lipid metabolism remains poorly understood. Here, we investigated the molecular mechanisms underlying matrine's regulation of lipid metabolism. Employing quantitative proteomics, we discovered that matrine increases the expression of LDL receptor (LDLR) in HepG2 and A549 cells, with subsequent experiments validating its role in enhancing LDL uptake. Notably, in hyperlipidemic hamsters, matrine effectively lowered lipid levels without affecting body weight, which highlights LDLR as a critical target for matrine's impact on HLP. Moreover, matrine's potential inhibitory effects on tumor cell LDL uptake hint at broader applications in cancer research. Additionally, thermal proteome profiling analysis identified lipid metabolism-related proteins that may interact with matrine. Together, our study reveals matrine's capacity to upregulate LDLR expression and highlights its potential in treating HLP. These findings offer insights into matrine's mechanism of action and open new avenues for drug research and lipid metabolism regulation.

Gut microbiota: a potential influencer of insomnia occurring after COVID-19 infection.

The prevalence of insomnia has increased in recent years, significantly affecting the lives of many individuals. Coronavirus disease 2019 (COVID-19) infection has been found to have a substantial impact on the human gut microbiota (GM). Clinical studies have shown that the high prevalence, prolonged duration, and refractory treatment of insomnia symptoms following the COVID-19 pandemic may be related to the effect of COVID-19 infection on the GM. Therefore, the GM may be a potential target for the treatment of insomnia following COVID-19 infection. However, relevant studies have not been well-documented, and the GM has not been sufficiently analyzed in the context of insomnia treatment. Herein, we review the interaction between sleep and the GM, summarize the characteristics of COVID-19-induced abnormal changes in the GM and metabolites in patients with insomnia, and discuss potential mechanisms, including metabolic, immune, and neural pathways, by which these abnormal changes in the GM cause insomnia as well as the factors affecting the GM. Finally, we discuss the prospect of modulating the host GM community for the effective treatment of insomnia after COVID-19 infection and the need for further clinical studies.

Neural correlates of stimulus spatial frequency-dependent contrast detection.

UNLABELLED: Psychophysical studies on human and non-human vertebrate species have shown that visual contrast sensitivity function (CSF) peaks at a certain stimulus spatial frequency and declines in both lower and higher spatial frequencies. The underlying neural substrate and mechanisms remain in debate. Here, we investigated the role of primary visual cortex (V1: area 17) in spatial frequency-dependent contrast detection in cats. Perceptual CSFs of three cats were measured using a two-alternative forced-choice task. The responses of V1 neurons to their optimal visual stimuli in a range of luminance contrast levels (from 0 to 1.0) were recorded subsequently using in vivo extracellular single-unit recording techniques. The contrast sensitivity of each neuron was determined. The neuronal CSF for each cat was constructed from the mean contrast sensitivity of neurons with different preferred stimulus spatial frequencies. RESULT: (1) The perceptual and neuronal CSFs of each of the three cats exhibited a similar shape with peak amplitude near 0.4 cpd. (2) The neuronal CSF of each cat was highly correlated with its perceptual CSF. (3) V1 neurons with different preferred stimulus spatial frequencies had different contrast gains. CONCLUSION: (1) Contrast detection of visual stimuli with different spatial frequencies may likely involve population coding of V1 neurons with different preferred stimulus spatial frequencies. (2) Difference in contrast gain may underlie the observed contrast sensitivity variation of V1 neurons with different preferred stimulus spatial frequencies, possibly from either evolution or postnatal visual experiences.

Role of sorbent surface functionalities and microporosity in 2,2',4,4'-tetrabromodiphenyl ether sorption onto biochars.

The study provides insight into the combined effect of sorbent surface functionalities and microporosity on 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) sorption onto biochars. A series of biochars prepared under different conditions were used to test their sorption behaviors with BDE-47. The extents of sorption behaviors were parameterized in terms of the single-point adsorption equilibrium constant (Koc) at three equilibrium concentration (Ce) levels (0.001Sw (solubility), 0.005Sw, and 0.05Sw) which was determined using the Freundlich model. To elucidate the concentration-dependent dominant mechanisms for BDE-47 sorption onto biochars, Ko was correlated with four major parameters using multiple parameter linear analysis accompanied with significance testing. The results indicated that at low concentration (Ce = 0.001Sw), the surface microporosity term, which represented a pore-filling mechanism, contributed significantly to this relationship, while as concentration was increased to higher levels, surface functionality related to surface adsorption began to take the dominant role, which was further confirmed by the results of Polanyi-based modeling. Given the above results, a dual mode model based on Dubinin-Radushkevich and de Boer-Zwikker equations was adopted to quantitatively assess the changes of significance of surface adsorption as well as that of pore filling with sorption process development. In addition, UV spectra of four typical aromatic compounds which represented the key structural fragments of biochars before and after interactions with BDE-47 were analyzed to determine the active functional groups and supply complementary evidence for the dominant interaction force for surface adsorption, based on which eta-eta electron-donor-acceptor interaction was proposed to contribute greatly to surface adsorption.

Development of machine learning models aiming at knee osteoarthritis diagnosing: an MRI radiomics analysis.

BACKGROUND: To develop and assess the performance of machine learning (ML) models based on magnetic resonance imaging (MRI) radiomics analysis for knee osteoarthritis (KOA) diagnosis. METHODS: This retrospective study analysed 148 consecutive patients (72 with KOA and 76 without) with available MRI image data, where radiomics features in cartilage portions were extracted and then filtered. Intraclass correlation coefficient (ICC) was calculated to quantify the reproducibility of features, and a threshold of 0.8 was set. The training and validation cohorts consisted of 117 and 31 cases, respectively. Least absolute shrinkage and selection operator (LASSO) regression method was employed for feature selection. The ML classifiers were logistic regression (LR), K-nearest neighbour (KNN) and support vector machine (SVM). In each algorithm, ten models derived from all available planes of three joint compartments and their various combinations were, respectively, constructed for comparative analysis. The performance of classifiers was mainly evaluated and compared by receiver operating characteristic (ROC) analysis. RESULTS: All models achieved satisfying performances, especially the Final model, where accuracy and area under ROC curve (AUC) of LR classifier were 0.968, 0.983 (0.957-1.000, 95% CI) in the validation cohort, and 0.940, 0.984 (0.969-0.995, 95% CI) in the training cohort, respectively. CONCLUSION: The MRI radiomics analysis represented promising performance in noninvasive and preoperative KOA diagnosis, especially when considering all available planes of all three compartments of knee joints.

The theoretical investigation of OH-induced degradation mechanisms of isoproturon.

Herbicides are widely applied in agriculture, which causes emerging concern for contaminating surface water and groundwater. The degradation of isoproturon, being a typical phenylurea herbicide, has been studied much with advanced oxidation processes. However, little information on the detailed degradation mechanism from the theoretical level is available. In the present work, the degradation mechanisms of OH-initiated reactions of isoproturon were studied at the MPWB1K/6-311+G(3df, 2p)//MPWB1K/6-31+G(d, p) level. The calculation results display that H-atom abstraction, ·OH addition, and ·OH substitution pathways are found for ·OH and isoproturon reactions. For H-atom abstractions, the results show that aliphatic H atoms are more easily abstracted by ·OH than the aromatic H atoms, and the pathway R6 has the lowest energy barrier of 6.65 kcal mol-1, indicating that H in the -CH3 group attached to the N2 atom could be most favorably abstracted. Six pathways for ·OH addition to the six sites of the phenyl ring are identified with low energy barriers, which are in good accordance with the fact that the additions of ·OH to the phenyl ring were the important steps from experimental results. For ·OH substitution reactions, two pathways with high activation energies are found, and the corresponding products have been also detected from previous experimental studies, suggesting that the substitution reactions could also occur.

Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance.

6-Phosphogluconate dehydrogenase (6PGD) is a key enzyme that converts 6-phosphogluconate into ribulose-5-phosphate with NADP+ as cofactor in the pentose phosphate pathway (PPP). 6PGD is commonly upregulated and plays important roles in many human cancers, while the mechanism underlying such roles of 6PGD remains elusive. Here we show that upon EGFR activation, 6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP+ and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. Abrogating 6PGD Y481 phosphorylation (pY481) dramatically attenuates EGF-promoted glioma cell proliferation, tumor growth and resistance to ionizing radiation. In addition, 6PGD pY481 is associated with Fyn expression, the malignancy and prognosis of human glioblastoma. These findings establish a critical role of Fyn-dependent 6PGD phosphorylation in EGF-promoted tumor growth and radiation resistance.

Phosphorylation of ULK1 affects autophagosome fusion and links chaperone-mediated autophagy to macroautophagy.

The Unc-51 like autophagy activating kinase 1 (ULK1) complex plays a central role in the initiation stage of autophagy. However, the function of ULK1 in the late stage of autophagy is unknown. Here, we report that ULK1, a central kinase of the ULK1 complex involved in autophagy initiation, promotes autophagosome-lysosome fusion. PKCα phosphorylates ULK1 and prevents autolysosome formation. PKCα phosphorylation of ULK1 does not change its kinase activity; however, it decreases autophagosome-lysosome fusion by reducing the affinity of ULK1 for syntaxin 17 (STX17). Unphosphorylated ULK1 recruited STX17 and increased STX17's affinity towards synaptosomal-associated protein 29 (SNAP29). Additionally, phosphorylation of ULK1 enhances its interaction with heat shock cognate 70 kDa protein (HSC70) and increases its degradation through chaperone-mediated autophagy (CMA). Our study unearths a key mechanism underlying autolysosome formation, a process in which the kinase activity of PKCα plays an instrumental role, and reveals the significance of the mutual regulation of macroautophagy and CMA in maintaining the balance of autophagy.

Nodulating Competitiveness of a Nonmotile Tn7 Mutant of Bradyrhizobium japonicum in Nonsterile Soil.

A nonmotile mutant of Bradyrhizobium japonicum serogroup 127 was generated by Tn7 mutagenesis and matched with the wild type against a common competitor in studies of soybean nodulation in nonsterile soil. The Tn7 mutant was very similar to the wild type in growth rate in culture, soybean lectin-binding ability, flagellar morphology, and nodulating capability, but it had a longer lag phase. Competing strains were distributed uniformly in soil in various ratios and at different population densities prior to planting. Mutant and wild type were equally prevalent in the seedling rhizosphere at about the time of nodule initiation, suggesting that motility conferred no advantage in rhizosphere colonization. Nodulation success of the Tn7 mutant was lower than that of the wild type under all test conditions. Differences were greatest at low soil populations of competitors and much less pronounced at initial populations of 10 g. The longer lag phase of the Tn7 mutant may have contributed to its decreased competitiveness, especially at the higher inoculation levels. The antibiotic and motility markers were stable, and the rifampin resistance derived from the parent did not affect adversely the competitiveness of the Tn7 mutant. We found motility to be of limited importance to the competitiveness of a strain in normal nonsterile soil, where the significance, if any, of this ability may be in migration at the immediate root surface in soils sparsely populated with rhizobial symbionts.

[Contributions of soil fauna to litter decomposition in alpine/subalpine forests].

A field experiment was conducted using the litterbag method to quantify the contribution of soil fauna to litter mass loss of Salix paraplesia, Sabina saltuaria, Betula albosinensis and Abies faxoniana during different key periods of the decomposition process of the first year (from November 2011 to October 2012). The results showed that the mass loss rate showed S. paraplesia > B. albosinensis > A. faxoniana > S. saltuaria, and the rate in the growing season was greater than in the freeze-thaw season. The contribution rate of soil fauna to the mass decomposition displayed as S. saltuaria (26.7%) > A. faxoniana (18.8%) > B. albosinensis (15.7%) > S. paraplesia (13.2%), which was higher in the freeze-thaw season than in the growing season for litter of B. albo-sinensis and A. faxoniana while vice versa for litter of B. albosinensis and A. faxoniana. The contribution of soil fauna was mainly related to organic C, P and N/P in the freeze-thaw season, while N, C/N, lignin and lignin/cellulose in the growing season.

Adaptation to visual stimulation modifies the burst firing property of V1 neurons.

The mean firing rate of visual cortical neurons is reduced after prolonged visual stimulation, but the underlying process by which this occurs as well as the biological significance of this phenomenon remains unknown. Computational neuroscience studies indicate that high-frequency bursts in stimulus-driven responses can be transmitted across synapses more reliably than isolated spikes, and thus may carry accurate stimulus-related information. Our research examined whether or not adaptation affects the burst firing property of visual cortical neurons by examining changes in the burst firing changes of V1 neurons during adaptation to the preferred visual stimulus. The results show that adaptation to prolonged visual stimulation significantly decreased burst frequency (bursts/s) and burst length (spikes/burst), but increased burst duration and the interspike interval within bursts. These results suggest that the adaptation of V1 neurons to visual stimulation may result in a decrease of feedforward response gain but an increase of functional activities from lateral and/or feedback connections, which could lead to a reduction in the effectiveness of adapted neurons in transmitting information to its driven neurons.

Acute lesions of primary visual cortical areas in adult cats inactivate responses of neurons in higher visual cortices.

Psychophysical studies suggest that lateral extrastriate visual cortical areas in cats may mediate the sparing of vision largely by network reorganization following lesions of early visual cortical areas. To date, however, there is little direct physiological evidence to support this hypothesis. Using in vivo single-unit recording techniques, we examined the response of neurons in areas 19, 21, and 20 to different types of visual stimulation in cats with or without acute bilateral lesions in areas 17 and 18. Our results showed that, relative to the controls, acute lesions inactivated the response of 99.3% of neurons to moving gratings and 93% of neurons to flickering square stimuli in areas 19, 21, and 20. These results indicated that acute lesions of primary visual areas in adult cats may impair most visual abilities. Sparing of vision in cats with neonatal lesions in early visual cortical areas may result largely from a postoperative reorganization of visual pathways from subcortical nucleus to extrastriate visual cortical areas.