Adipokines secreted from white adipose tissue play a role in metabolic crosstalk and homeostasis, whereas the brown adipose secretome is less explored. We performed high-sensitivity ...mass-spectrometry-based proteomics on the cell media of human adipocytes derived from the supraclavicular brown adipose and from the subcutaneous white adipose depots of adult humans. We identified 471 potentially secreted proteins covering interesting categories such as hormones, growth factors, extracellular matrix proteins, and proteins of the complement system, which were differentially regulated between brown and white adipocytes. A total of 101 proteins were exclusively quantified in brown adipocytes, and among these was ependymin-related protein 1 (EPDR1). EPDR1 was detected in human plasma, and functional studies suggested a role for EPDR1 in thermogenic determination during adipogenesis. In conclusion, we report substantial differences between the secretomes of brown and white human adipocytes and identify novel candidate batokines that can be important regulators of human metabolism.
Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of ...murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA-knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ to control the brown fat gene program.
Abstract Objective MicroRNAs (miRNAs) are increasingly recognized as fine-tuning regulators of metabolism, and are dysregulated in several disease conditions. With their capacity to rapidly change ...gene expression, miRNAs are also important regulators of development and cell differentiation. In the current study, we describe an impaired myogenic capacity of muscle stem cells isolated from humans with type 2 diabetes (T2DM) and assess whether this phenotype is regulated by miRNAs. Methods We measured global miRNA expression during in vitro differentiation of muscle stem cells derived from T2DM patients and healthy controls. Results The mir-23b/27b cluster was downregulated in the cells of the patients, and a pro-myogenic effect of these miRNAs was mediated through the p53 pathway, which was concordantly dysregulated in the muscle cells derived from humans with T2DM. Conclusions Our results indicate that we have identified a novel pathway for coordination of myogenesis, the miR-23b/27b-p53 axis that, when dysregulated, potentially contributes to a sustained muscular dysfunction in T2DM.
A novel technique has been developed, which will open exciting new opportunities for studying the very neutron-rich nuclei involved in the r process. As a proof of principle, the γ spectra from the β ...decay of ^{76}Ga have been measured with the SuN detector at the National Superconducting Cyclotron Laboratory. The nuclear level density and γ-ray strength function are extracted and used as input to Hauser-Feshbach calculations. The present technique is shown to strongly constrain the ^{75}Ge(n,γ)^{76}Ge cross section and reaction rate.
How many human proteoforms are there? Aebersold, Ruedi; Agar, Jeffrey N; Amster, I Jonathan ...
Nature chemical biology,
02/2018, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One ...of the most fundamental queries is the extent to which the combinations of DNA-, RNA- and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.
The photoneutron cross sections of 162,163Dy have been measured for the first time in an energy region from the neutron threshold (Sn) up to ≈13MeV. The (γ,n) reaction was induced with ...quasimonochromatic laser Compton-scattered γ rays, produced at the NewSUBARU laboratory. The corresponding γ -ray strength functions (γ SF) have been calculated from the photoneutron cross sections. The data are compared to reanalyzed γSFs of 160–164Dy, which are measured below Sn. The excellent agreement with the photoneutron data at Sn confirms the principle of detailed balance. Thus, a complete γ SF is established covering in total the energy regionof1 Eγ 13MeV.Thesemid-shellwell-deformeddysprosiumisotopesallshowscissorsresonances with very similar structures. We find that our data predict the same integrated scissors strength as (γ,γ′) data when integrated over the same energy range, which shows that the scissors mode very likely is consistent with the generalized Brink hypothesis. Finally, using the γSFs as input in the reaction code TALYS, we have deduced radiative neutron-capture cross sections and compared them to direct measurements. We find a very good agreement within the uncertainties, which gives further support to the experimentally determined γ SFs.
Prolonged physical inactivity in young adults may lead to deficiencies in musculoskeletal fitness, and thus a need exists to develop physical activity and exercise programmes that are effective of ...increasing musculoskeletal fitness. The aim of this study, therefore, was to investigate the effects of small-sided team handball training on lower limb muscle strength, postural balance and body composition in young adults. Twenty-six men and twenty-eight women were stratified for peak oxygen uptake (VO2peak) and body fat percentage and randomly allocated to either 12 wks of small-sided recreational team handball training (THG: 14 men and 14 women, age 24.1±2.6 yrs (mean±SD), VO2peak 39.8±5.9 ml/kg/min and body fat percentage 32.7±8.7%) or serving as non-exercising controls (CON: 12 men and 14 women, age 24.8±3.1 yrs, VO2peak 39.7±5.0 ml/kg/min, body fat percentage 31.7±9.7%). THG trained on average 1.8 times/week for 12 wks. At 0 and 12 wks, lower limb muscle strength, rate of force development (RFD), vertical jump height and power, postural balance, body composition and muscle biopsies were assessed. No training effects were observed for maximal isokinetic or isometric knee extensor strength, maximal vertical jump height or take-off power, fibre type distribution or capillarization. Late phase (RFD) increased (+7.4%, p<0.05) and postural sway excursion length was improved after training (-9%, p<0.05) in THG with no difference from CON (p>0.05). Further, THG demonstrated a decrease in body fat percentage (-3.7%) accompanied by increases in whole-body fat free mass (FFM) (+2.2%), leg FFM (+2.5%), total bone mineral content (BMC) (+1.1%), leg BMC (+1.2%), total hip bone mineral density (+1.6%) and hip T-score (+50%) which differed from CON (all p<0.05). In conclusion, recreational small-sided team handball training appears to effectively improve rapid force capacity, postural balance, lean and fat body mass and bone health in previously untrained young adults. The study was registered at ClinicalTrials.gov (NCT04247724). ClinicalTrials.gov ID number: NCT04247724.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have made a thorough study of the low-energy behavior of the γ -ray strength function within the framework of the shell model. We have performed large-scale calculations spanning isotopic and ...isotonic chains over several mass regions, considering 283 nuclei in total, with the purpose of studying the systematic behavior of the low-energy enhancement (LEE) for M1 transitions. There are clear trends in the calculations: From being nearly absent in the lowest mass region, the LEE becomes steeper and more pronounced as the mass number increases, and for a given mass region it further increases toward shell closures. Moreover, the LEE is found to be steeper in regions near doubly magic nuclei where proton particles couple to neutron holes. These trends enable us to consolidate several previous works on the LEE into a single, consistent concept. We compare the inferred trends to the available experimental data from the Oslo method and find support for the systematic behavior. Lastly, we have compared the calculations to strength functions compiled from discrete, experimental lifetimes and find excellent agreement; the discrete data are consistent with an LEE and indicate that the slope varies as function of mass number.
The initiation of systemic antimicrobial treatment of Pneumocystis jirovecii pneumonia (PCP) is triggered by clinical signs and symptoms, typical radiological and occasionally laboratory findings in ...patients at risk of this infection. Diagnostic proof by bronchoalveolar lavage should not delay the start of treatment. Most patients with haematological malignancies present with a severe PCP; therefore, antimicrobial therapy should be started intravenously. High-dose trimethoprim/sulfamethoxazole is the treatment of choice. In patients with documented intolerance to this regimen, the preferred alternative is the combination of primaquine plus clindamycin. Treatment success should be first evaluated after 1 week, and in case of clinical non-response, pulmonary CT scan and bronchoalveolar lavage should be repeated to look for secondary or co-infections. Treatment duration typically is 3 weeks and secondary anti-PCP prophylaxis is indicated in all patients thereafter. In patients with critical respiratory failure, non-invasive ventilation is not significantly superior to intubation and mechanical ventilation. The administration of glucocorticoids must be decided on a case-by-case basis.
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