Heteroatom doped atomically dispersed Fe1‐NC catalysts have been found to show excellent activity toward oxygen reduction reaction (ORR). However, the origin of the enhanced activity is still ...controversial because the structure‐function relationship governing the enhancement remains elusive. Herein, sulfur(S)‐doped Fe1‐NC catalyst was obtained as a model, which displays a superior activity for ORR towards the traditional Fe‐NC materials. 57Fe Mössbauer spectroscopy and electron paramagnetic resonance spectroscopy revealed that incorporation of S in the second coordination sphere of Fe1‐NC can induce the transition of spin polarization configuration. Operando 57Fe Mössbauer spectra definitively identified the low spin single‐Fe3+‐atom of C‐FeN4‐S moiety as the active site for ORR. Moreover, DFT calculations unveiled that lower spin state of the Fe center after the S doping promotes OH* desorption process. This work elucidates the underlying mechanisms towards S doping for enhancing ORR activity, and paves a way to investigate the function of broader heteroatom doped Fe1‐NC catalysts to offer a general guideline for spin‐state‐determined ORR.
The enhanced oxygen reduction reaction (ORR) activity of sulfur‐doped Fe‐N‐C single‐atom catalysts is studied from Fe spin‐state tuning. Operando 57Fe Mössbauer spectra monitoring further supported the low‐spin (LS) single‐Fe3+‐atom of the C‐FeN4‐S moiety as the active site for the ORR.
Masticatory muscle thickness provides objective measurements of the oral motor function, which may change in patients with oral myofascial pain. In this study, we aimed to establish a reliable ...ultrasound (US) protocol for imaging the superficial and deep masticatory muscles and to identify the potential influencers of the measurements. Forty-eight healthy participants without orofacial pain were enrolled. The intra-and inter-rater reliabilities of US measurements for masseter, temporalis, and lateral pterygoid muscles were assessed. Intraclass correlation coefficients for all muscles were greater than 0.6. The generalised estimating equation was used to analyse the impact of age, gender, laterality, and body mass index on the measurements, whereby age and body mass index were likely to be associated with an increase in masticatory muscle thickness. The thickness tended to be lesser in females. Laterality seemed to exert minimal influence on masticatory muscle thickness. Our study shows acceptable reliability of US in the evaluation of superficial and deep masticatory muscle thickness. Future studies are warranted to validate the usefulness of US imaging in patients with oral myofascial pain syndrome.
Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide ...variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over‐expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type‐specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β‐cells exposed to fatty acids, and survival of FAO‐dependent lymphoma subtypes. We find that fragmentation increases long‐chain but not short‐chain FAO, identifying carnitine O‐palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl‐CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl‐CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.
Synopsis
Metabolic fuel preference is associated with mitochondrial architecture, yet the mechanisms that connect shape and function remain unknown. This study demonstrates selective coupling between mitochondrial architecture and fatty acid (FA) utilization, uncovering an unexpected connection between mitochondrial fusion and fission, and fuel choice.
Long‐chain FA oxidation capacity increases upon mitochondrial fragmentation and decreases upon mitochondrial elongation.
Activity of CPT1, a rate‐limiting enzyme in fatty acid oxidation, is inhibited by the elongation of mitochondria, but enhanced by their fragmentation.
Mitochondrial fragmentation reduces CPT1's sensitivity to its endogenous inhibitor, malonyl‐CoA, which is a product of pyruvate metabolism and the first metabolite in FA synthesis.
Fragmentation‐induced FA utilization has cell type‐specific functional consequences, causing increased hepatic gluconeogenesis, induction of insulin secretion at non‐stimulatory glucose levels, and enhanced survival of OXPHOS‐dependent lymphoma cells.
Mitochondrial fragmentation increases beta‐oxidation and cellular lipid metabolism via de‐repressing CPT1.
Axicabtagene ciloleucel (axi-cel) was approved by the Food and Drug Administration for relapsed aggressive B-cell non-Hodgkin lymphoma in part on the basis of durable remission rates of approximately ...40% in a clinical trial population. Whether this efficacy, and the rates of toxicity, would be consistent in a postcommercial setting, with relaxed eligibility criteria and bridging therapy, is unknown. This study describes the efficacy and safety correlates and outcomes in this setting.
One hundred twenty-two patients from 7 medical centers in the United States were treated with axi-cel and were included in a modified intent-to-treat (mITT) analysis. Seventy-six patients (62%) were ineligible for the ZUMA-1 trial. Response and toxicity rates, duration of response (DOR), survival, and covariates are described on the basis of the mITT population. Correlative studies on blood and tumor samples were performed to investigate potential biomarkers of response and resistance.
Median follow-up was 10.4 months. In the mITT population, the best overall and complete response (CR) rates were 70% and 50%, respectively. Median DOR and progression-free survival (PFS) were 11.0 and 4.5 months in all patients and were not reached (NR) in CR patients. Median overall survival (OS) was NR; 1-year OS was 67% (95% CI, 59% to 77%). Although response rates were similar in the ZUMA-1-eligible and ZUMA-1-ineligible groups (70%
68%), there was a statistically significant improvement in CR rate (63%
42%,
= .016), DOR (median, NR
5.0 months;
= .014), PFS (median, NR
3.3 months;
= .020), and OS (1-year OS, 89%
54%;
< .001) in patients who were ZUMA-1 eligible. Rates of grade ≥ 3 cytokine release syndrome and neurotoxicty were 16% and 35%, respectively.
Axi-cel yields similar rates of overall response and toxicity in commercial and trial settings, although CR rates and DOR were more favorable in patients eligible for ZUMA-1.
Nonalcoholic fatty liver disease (NAFLD) is a common metabolic syndrome. Imbalances between liver lipid output and input are the direct causes of NAFLD, and hepatic steatosis is the pathological ...premise and basis for NAFLD progression. Mutual interaction between endoplasmic reticulum stress (ERS) and oxidative stress play important roles in NAFLD pathogenesis. Notably, mitochondria-associated membranes (MAMs) act as a structural bridges for functional clustering of molecules, particularly for Ca
, lipids, and reactive oxygen species (ROS) exchange. Previous studies have examined the crucial roles of ERS and ROS in NAFLD and have shown that MAM structural and functional integrity determines normal ER- mitochondria communication. Upon disruption of MAM integrity, miscommunication directly or indirectly causes imbalances in Ca2+ homeostasis and increases ERS and oxidative stress. Here, we emphasize the involvement of MAMs in glucose and lipid metabolism, chronic inflammation and insulin resistance in NAFLD and summarize MAM-targeting drugs and compounds, most of which achieve their therapeutic or ameliorative effects on NAFLD by improving MAM integrity. Therefore, targeting MAMs may be a viable strategy for NAFLD treatment. This review provides new ideas and key points for basic NAFLD research and drug development centred on mitochondria and the endoplasmic reticulum.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To understand the mechanism(s) of age‐dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age‐related HBV mouse model in which 6‐week‐old (N6W) C3H/HeN ...mice exhibited virus tolerance whereas 12‐week‐old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C‐C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF‐α–secreting Ly6C+ monocytes and fewer IL‐10–secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon‐γ+TNF‐α+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W mice resulted from elevated C‐C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV‐related liver diseases.
Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes, including signal transduction and gene expression patterns, arising from specific oncogenotypes and cell ...lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here, we quantified metabolic features, mostly from the 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression, and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.
Display omitted
•Cell-autonomous metabolic diversity is reported in over 80 lung cancer cell lines•Heterogeneous metabolic phenotypes support lung cancer cell growth•Relating metabolic and molecular data uncovers new aspects of metabolic regulation•Some metabolic features predict sensitivity to chemotherapy and targeted agents
Metabolic reprogramming influences therapeutic sensitivity in cancer, but the scope of metabolic diversity among cancer cells is unknown. Chen et al. characterized metabolic phenotypes in over 80 non-small cell lung cancer cell lines and then used genomics, transcriptomics, proteomics, and therapeutic sensitivities to uncover relationships between metabolism and orthogonal processes.
Influences of intraseasonal–interannual oscillations on tropical cyclone (TC) genesis are evaluated by productivity of TC genesis (P
TCG) from the developing (TCd) and nondeveloping (TCn) precursory ...tropical disturbances (PTDs). A PTD is identified by a cyclonic tropical disturbance with a strong-enough intensity, a large-enough maximum center, and a long-enough lifespan. The percentage value of PTDs evolving into TCd is defined as P
TCG. The analysis is performed over the western North Pacific (WNP) basin during the 1990–2014 warm season (May–September). The climatological P
TCG in the WNP basin is 0.35. Counted in a common period, mean numbers of PTDs in the favorable and unfavorable conditions of climate oscillations for TC genesis such as equatorial Rossby waves (ERWs), the Madden–Julian oscillation (MJO), and El Niño–Southern Oscillation (ENSO), all exhibit a stable value close to the climatological mean ∼31 (100 days)−1. However, P
TCG increases (decreases) during the phases of positive-vorticity (negative-vorticity) ERWs, the active (inactive)MJO, and El Niño (La Niña) years. P
TCG varies from 0.17 in the most unfavorable environment (La Niña, inactive MJO, and negative-vorticity ERW) to 0.56 in the most favorable environment (El Niño, active MJO, and positive-vorticity ERW). ERWs are most effective in modulating TC genesis, especially in the negative-vorticity phases. Overall, increased P
TCG is facilitated with strong and elongated 850-hPa relative vorticity overlapping a cyclonic shear line pattern, while decreased P
TCG is related to weak relative vorticity. Relative vorticity acts as the most important factor to modulate P
TCG, when compared with vertical wind shear and 700-hPa relative humidity.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
mTOR, the mammalian target of rapamycin, integrates growth factor and nutrient signals to promote a transformation from catabolic to anabolic metabolism, cell growth, and cell cycle progression. ...Phosphatidic acid (PA) interacts with the FK506-binding protein–12-rapamycin-binding (FRB) domain of mTOR, which stabilizes both mTOR complexes: mTORC1 and mTORC2. We report here that mTORC1 and mTORC2 are activated in response to exogenously supplied fatty acids via the de novo synthesis of PA, a central metabolite for membrane phospholipid biosynthesis. We examined the impact of exogenously supplied fatty acids on mTOR in KRas-driven cancer cells, which are programmed to utilize exogenous lipids. The induction of mTOR by oleic acid was dependent upon the enzymes responsible for de novo synthesis of PA. Suppression of the de novo synthesis of PA resulted in G1 cell cycle arrest. Although it has long been appreciated that mTOR is a sensor of amino acids and glucose, this study reveals that mTOR also senses the presence of lipids via production of PA.
PDF
