The role of C17:0 and C15:0 in human health has recently been reinforced following a number of important biological and nutritional observations. Historically, odd chain saturated fatty acids ...(OCS-FAs) were used as internal standards in GC-MS methods of total fatty acids and LC-MS methods of intact lipids, as it was thought their concentrations were insignificant in humans. However, it has been thought that increased consumption of dairy products has an association with an increase in blood plasma OCS-FAs. However, there is currently no direct evidence but rather a casual association through epidemiology studies. Furthermore, a number of studies on cardiometabolic diseases have shown that plasma concentrations of OCS-FAs are associated with lower disease risk, although the mechanism responsible for this is debated. One possible mechanism for the endogenous production of OCS-FAs is α-oxidation, involving the activation, then hydroxylation of the α-carbon, followed by the removal of the terminal carboxyl group. Differentiation human adipocytes showed a distinct increase in the concentration of OCS-FAs, which was possibly caused through α-oxidation. Further evidence for an endogenous pathway, is in human plasma, where the ratio of C15:0 to C17:0 is approximately 1:2 which is contradictory to the expected levels of C15:0 to C17:0 roughly 2:1 as detected in dairy fat. We review the literature on the dietary consumption of OCS-FAs and their potential endogenous metabolism.
Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a ...shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.
ABSTRACT
We determine rotation periods for 127 stars in the ∼115-Myr-old Blanco 1 open cluster using ∼200 d of photometric monitoring with the Next Generation Transit Survey. These stars span F5–M3 ...spectral types (1.2 M⊙ ≳ M ≳ 0.3 M⊙) and increase the number of known rotation periods in Blanco 1 by a factor of four. We determine rotation periods using three methods: Gaussian process (GP) regression, generalized autocorrelation function (G-ACF), and Lomb–Scargle (LS) periodogram, and find that the GP and G-ACF methods are more applicable to evolving spot modulation patterns. Between mid-F and mid-K spectral types, single stars follow a well-defined rotation sequence from ∼2 to 10 d, whereas stars in photometric multiple systems typically rotate faster. This may suggest that the presence of a moderate-to-high mass ratio companion inhibits angular momentum loss mechanisms during the early pre-main sequence, and this signature has not been erased at ∼100 Myr. The majority of mid-F to mid-K stars display evolving modulation patterns, whereas most M stars show stable modulation signals. This morphological change coincides with the shift from a well-defined rotation sequence (mid-F to mid-K stars) to a broad rotation period distribution (late-K and M stars). Finally, we compare our rotation results for Blanco 1 to the similarly aged Pleiades: the single-star populations in both clusters possess consistent rotation period distributions, which suggests that the angular momentum evolution of stars follows a well-defined pathway that is, at least for mid-F to mid-K stars, strongly imprinted by ∼100 Myr.
Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the ...precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is imperative to develop more efficient processes for conversion of biomass to liquid fuels, such that the cost of these fuels would be competitive with the cost of fuels derived from petroleum. ...We report a catalytic approach for the conversion of carbohydrates to specific classes of hydrocarbons for use as liquid transportation fuels, based on the integration of several flow reactors operated in a cascade mode, where the effluent from the one reactor is simply fed to the next reactor. This approach can be tuned for production of branched hydrocarbons and aromatic compounds in gasoline, or longer-chain, less highly branched hydrocarbons in diesel and jet fuels. The liquid organic effluent from the first flow reactor contains monofunctional compounds, such as alcohols, ketones, carboxylic acids, and heterocycles, that can also be used to provide reactive intermediates for fine chemicals and polymers markets.
Metabolic basis to Sherpa altitude adaptation Horscroft, James A.; Kotwica, Aleksandra O.; Laner, Verena ...
Proceedings of the National Academy of Sciences - PNAS,
06/2017, Letnik:
114, Številka:
24
Journal Article
Recenzirano
Odprti dostop
The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison ...to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.
Chlamydia pneumoniae is a respiratory tract pathogen but can also infect the central nervous system (CNS). Recently, the link between C. pneumoniae CNS infection and late-onset dementia has become ...increasingly evident. In mice, CNS infection has been shown to occur weeks to months after intranasal inoculation. By isolating live C. pneumoniae from tissues and using immunohistochemistry, we show that C. pneumoniae can infect the olfactory and trigeminal nerves, olfactory bulb and brain within 72 h in mice. C. pneumoniae infection also resulted in dysregulation of key pathways involved in Alzheimer's disease pathogenesis at 7 and 28 days after inoculation. Interestingly, amyloid beta accumulations were also detected adjacent to the C. pneumoniae inclusions in the olfactory system. Furthermore, injury to the nasal epithelium resulted in increased peripheral nerve and olfactory bulb infection, but did not alter general CNS infection. In vitro, C. pneumoniae was able to infect peripheral nerve and CNS glia. In summary, the nerves extending between the nasal cavity and the brain constitute invasion paths by which C. pneumoniae can rapidly invade the CNS likely by surviving in glia and leading to Aβ deposition.
Extracellular vesicles (EVs) harbor thousands of proteins that hold promise for biomarker development. Usually difficult to purify, EVs in urine are relatively easily obtained and have demonstrated ...efficacy for kidney disease prediction. Herein, we further characterize the proteome of urinary EVs to explore the potential for biomarkers unrelated to kidney dysfunction, focusing on Parkinson's disease (PD).
Using a quantitative mass spectrometry approach, we measured urinary EV proteins from a discovery cohort of 50 subjects. EVs in urine were classified into subgroups and EV proteins were ranked by abundance and variability over time. Enriched pathways and ontologies in stable EV proteins were identified and proteins that predict PD were further measured in a cohort of 108 subjects.
Hundreds of commonly expressed urinary EV proteins with stable expression over time were distinguished from proteins with high variability. Bioinformatic analyses reveal a striking enrichment of endolysosomal proteins linked to Parkinson's, Alzheimer's, and Huntington's disease. Tissue and biofluid enrichment analyses show broad representation of EVs from across the body without bias towards kidney or urine proteins. Among the proteins linked to neurological diseases, SNAP23 and calbindin were the most elevated in PD cases with 86% prediction success for disease diagnosis in the discovery cohort and 76% prediction success in the replication cohort.
Urinary EVs are an underutilized but highly accessible resource for biomarker discovery with particular promise for neurological diseases like PD.
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