The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that ...exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.
Bacterial biofilms in the colon alter the host tissue microenvironment. A role for biofilms in colon cancer metabolism has been suggested but to date has not been evaluated. Using metabolomics, we ...investigated the metabolic influence that microbial biofilms have on colon tissues and the related occurrence of cancer. Patient-matched colon cancers and histologically normal tissues, with or without biofilms, were examined. We show the upregulation of polyamine metabolites in tissues from cancer hosts with significant enhancement of N1, N12-diacetylspermine in both biofilm-positive cancer and normal tissues. Antibiotic treatment, which cleared biofilms, decreased N1, N12-diacetylspermine levels to those seen in biofilm-negative tissues, indicating that host cancer and bacterial biofilm structures contribute to the polyamine metabolite pool. These results show that colonic mucosal biofilms alter the cancer metabolome to produce a regulator of cellular proliferation and colon cancer growth potentially affecting cancer development and progression.
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•Colonic mucosal biofilms alter the cancer metabolome•N1, N12-diacetylspermine was significantly upregulated in tissues with biofilms•Biofilms create conditions conducive to oncogenic transformation in colon cells•Global isotope metabolomics reveals the metabolite fate of N1, N12-diacetylspermine
Johnson et al. examine the metabolomics of bacterial communities called biofilms and human colon cancers. The host and bacterial polyamine metabolites are proposed to act together to promote biofilm formation and cancer growth, creating conditions conducive for normal to cancer cell transformation.
Tumors are comprised of a multitude of cell types spanning different microenvironments. Mass spectrometry imaging (MSI) has the potential to identify metabolic patterns within the tumor ecosystem and ...surrounding tissues, but conventional workflows have not yet fully integrated the breadth of experimental techniques in metabolomics. Here, we combine MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to map distributions of metabolite abundances, nutrient contributions, and metabolic turnover fluxes across the brains of mice harboring GL261 glioma, a widely used model for glioblastoma. When integrated with MSI, the combination of ion mobility, desorption electrospray ionization, and matrix assisted laser desorption ionization reveals alterations in multiple anabolic pathways. De novo fatty acid synthesis flux is increased by approximately 3-fold in glioma relative to surrounding healthy tissue. Fatty acid elongation flux is elevated even higher at 8-fold relative to surrounding healthy tissue and highlights the importance of elongase activity in glioma.
The poor quality of SiC/SiO2 interface significantly limits the channel mobility, especially in 4H-SiC MOSFETs. Several strategies have been addressed to overcome this issue. Nitridation by NO has ...been adopted widely by manufactures because nitrogen may replace carbon in some chemical bond at the SiC/SiO2 interface. However, excessive nitridation is not desirable because of pronounced hole-trapping effects near the conduction band. As an alternative gate dielectric, thin SiO2/deposited oxide stack has been investigated in 4H-SiC lateral nMOSFETs. Overall performances were reviewed in aspects of transfer/gm/reverse characteristics, charge pumping method and TLP characteristics.
Abnormal thalamocortical networks involving specific thalamic nuclei have been implicated in schizophrenia pathophysiology. While comparable topography of anatomical and functional connectivity ...abnormalities has been reported in patients across illness stages, previous functional studies have been confined to anatomical pathways of thalamocortical networks. To address this issue, we incorporated large-scale brain network dynamics into examining thalamocortical functional connectivity. Forty patients with first-episode psychosis and forty healthy controls underwent T1-weighted and resting-state functional magnetic resonance imaging. Independent component analysis of voxelwise thalamic functional connectivity maps parcellated the cortex into thalamus-related networks, and thalamic subdivisions associated with these networks were delineated. Functional connectivity of (1) networks with the thalamus and (2) thalamic subdivision seeds were examined. In patients, functional connectivity of the salience network with the thalamus was decreased and localized to the ventrolateral (VL) and ventroposterior (VP) thalamus, while that of a network comprising the cerebellum, temporal and parietal regions was increased and localized to the mediodorsal (MD) thalamus. In patients, thalamic subdivision encompassing the VL and VP thalamus demonstrated hypoconnectivity and that encompassing the MD and pulvinar regions demonstrated hyperconnectivity. Our results extend the implications of disrupted thalamocortical networks involving specific thalamic nuclei to dysfunctional large-scale brain network dynamics in schizophrenia pathophysiology.
Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation ...is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1
), arrests osteoclast function but not formation. Bap1
osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.
Normocalcaemic primary hyperparathyroidism (NPHPT) is often under-recognised in clinical practice.
To determine the prevalence and clinical significance of NPHPT in an unselected sample in an acute ...hospital setting.
Patients aged >18 years who had measurement of an elevated serum parathyroid hormone (PTH ≥ 7 pmol/L) during 12 months from 1 January 2017 to 31 December 2017 were retrospectively studied. NPHPT was defined by the presence of elevated serum PTH with normal albumin-corrected serum calcium on two or more occasions after excluding secondary causes. Patients were followed up for 2 years. Relevant data were collected by review of electronic medical records.
Of the 2593 patients who had PTH measured during the study period, 1278 had serum PTH ≥ 7 pmol/L. Hypercalcaemic primary hyperparathyroidism (PHPT) was diagnosed in 174 patients. Secondary causes for elevated serum PTH were identified in 993 patients: 815 (chronic kidney disease - estimated glomerular filtration rate < 60 mL/min/1.73 m
or renal transplant), 98 (vitamin D deficiency - 25(OH)D < 50 nmol/L), 28 (gastric bypass surgery), 38 (medications), 13 (malabsorption or post-thyroidectomy) and 1 (hypercalciuria). Data were incomplete for 80 patients. The prevalence of NPHPT with and without the exclusion of hypercalciuria was 0.19% (5) and 0.39% (10) respectively. The prevalence of nephrolithiasis in NPHPT was higher than PHPT (100% vs 15% among five patients (P < 0.001) and 50% vs 15% among 10 patients (P = 0.014)). The prevalence of osteoporosis was not significantly different between NPHPT and PHPT (20% vs 45% among five patients (P = 0.389) and 30% vs 45% among 10 patients (P = 0.518)).
These findings give further credence to the diagnosis of NPHPT as a clinical entity. Nephrolithiasis may be a greater problem than osteoporosis in NPHPT compared with PHPT. This needs prospective evaluation.
Highlights • Schizophrenic patients and clinical high risk subjects show decreased mismatch negativity (MMN) strength in frontal and temporal cortices. • Disconnection between MMN-related brain ...regions exists even prior to psychosis onset. • Aberrant MMN generator activity might be related to schizophrenia pathophysiology.
The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary ...cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.
Oxidation of the FeIII complex (TBP8Cz)FeIII TBP8Cz = octakis(4-tert-butylphenyl)corrolazinate with O-atom transfer oxidants under a variety of conditions gives the reactive high-valent Fe(O) complex ...(TBP8Cz+•)FeIV(O) (2). The solution state structure of 2 was characterized by XAS d(Fe–O) = 1.64 Å. This complex is competent to oxidize a range of C–H substrates. Product analyses and kinetic data show that these reactions occur via rate-determining hydrogen-atom transfer (HAT), with a linear correlation for log k versus BDE(C–H), and the following activation parameters for xanthene (Xn) substrate: ΔH ⧧ = 12.7 ± 0.8 kcal mol–1, ΔS ⧧ = −9 ± 3 cal K–1 mol–1, and KIE = 5.7. Rebound hydroxylation versus radical dimerization for Xn is favored by lowering the reaction temperature. These findings provide insights into the factors that control the intrinsic reactivity of Compound I heme analogues.
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