Glyco-biomarkers: Potential determinants of cellular physiology and pathology

Once dismissed as just the icing on the cake, sugar molecules are emerging as vital components in life’s intricate machinery. Our understanding of their function within the context of the proteins and lipids to which they are attached has matured rapidly, and with it the far reaching clinical implications are becoming understood. Recent advances in high-throughput glycomic techniques, glyco biomarker profiling, glyco-bioinformatics and development of increasingly sophisticated glyco-arrays, combined with our increased understanding of the molecular details of glycosylation have facilitated the linkage between aberrant glycosylation and human diseases, and highlighted the possibility of using glyco-biomarkers as potential determinants of disease and its progression. The focus of this review is to give an insight into the biological significance of these glycomodifications, highlight some specific examples of glyco-biomarkers in relation to autoimmunity and in particular rheumatoid arthritis, and to explore the exciting possibility of exploiting these for diagnostic and prognostic strategies

Radio Emission from Ultra-Cool Dwarfs

The 2001 discovery of radio emission from ultra-cool dwarfs (UCDs), the very low-mass stars and brown dwarfs with spectral types of ~M7 and later, revealed that these objects can generate and dissipate powerful magnetic fields. Radio observations provide unparalleled insight into UCD magnetism: detections extend to brown dwarfs with temperatures <1000 K, where no other observational probes are effective. The data reveal that UCDs can generate strong (kG) fields, sometimes with a stable dipolar structure; that they can produce and retain nonthermal plasmas with electron acceleration extending to MeV energies; and that they can drive auroral current systems resulting in significant atmospheric energy deposition and powerful, coherent radio bursts. Still to be understood are the underlying dynamo processes, the precise means by which particles are accelerated around these objects, the observed diversity of magnetic phenomenologies, and how all of these factors change as the mass of the central object approaches that of Jupiter. The answers to these questions are doubly important because UCDs are both potential exoplanet hosts, as in the TRAPPIST-1 system, and analogues of extrasolar giant planets themselves.Comment: 19 pages; submitted chapter to the Handbook of Exoplanets, eds. Hans J. Deeg and Juan Antonio Belmonte (Springer-Verlag

Large-scale features of Last Interglacial climate: Results from evaluating the lig127k simulations for the Coupled Model Intercomparison Project (CMIP6)-Paleoclimate Modeling Intercomparison Project (PMIP4)

Abstract. The modeling of paleoclimate, using physically based tools, is increasingly seen as a strong out-of-sample test of the models that are used for the projection of future climate changes. New to the Coupled Model Intercomparison Project (CMIP6) is the Tier 1 Last Interglacial experiment for 127 000 years ago (lig127k), designed to address the climate responses to stronger orbital forcing than the midHolocene experiment, using the same state-of-the-art models as for the future and following a common experimental protocol. Here we present a first analysis of a multi-model ensemble of 17 climate models, all of which have completed the CMIP6 DECK (Diagnostic, Evaluation and Characterization of Klima) experiments. The equilibrium climate sensitivity (ECS) of these models varies from 1.8 to 5.6 ∘C. The seasonal character of the insolation anomalies results in strong summer warming over the Northern Hemisphere continents in the lig127k ensemble as compared to the CMIP6 piControl and much-reduced minimum sea ice in the Arctic. The multi-model results indicate enhanced summer monsoonal precipitation in the Northern Hemisphere and reductions in the Southern Hemisphere. These responses are greater in the lig127k than the CMIP6 midHolocene simulations as expected from the larger insolation anomalies at 127 than 6 ka. New synthesis for surface temperature and precipitation, targeted for 127 ka, have been developed for comparison to the multi-model ensemble. The lig127k model ensemble and data reconstructions are in good agreement for summer temperature anomalies over Canada, Scandinavia, and the North Atlantic and for precipitation over the Northern Hemisphere continents. The model–data comparisons and mismatches point to further study of the sensitivity of the simulations to uncertainties in the boundary conditions and of the uncertainties and sparse coverage in current proxy reconstructions. The CMIP6–Paleoclimate Modeling Intercomparison Project (PMIP4) lig127k simulations, in combination with the proxy record, improve our confidence in future projections of monsoons, surface temperature, and Arctic sea ice, thus providing a key target for model evaluation and optimization. </jats:p

A prospective study of mental health care for comorbid depressed mood in older adults with painful osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Comorbid depression is common among adults with painful osteoarthritis (OA). We evaluated the relationship between depressed mood and receipt of mental health (MH) care services.</p> <p>Methods</p> <p>In a cohort with OA, annual interviews assessed comorbidity, arthritis severity, and MH (SF-36 mental health score). Surveys were linked to administrative health databases to identify mental health-related visits to physicians in the two years following the baseline interview (1996-98). Prescriptions for anti-depressants were ascertained for participants aged 65+ years (eligible for drug benefits). The relationship between MH scores and MH-related physician visits was assessed using zero-inflated negative binomial regression, adjusting for confounders. For those aged 65+ years, logistic regression examined the probability of receiving <it>any </it>MH-related care (physician visit or anti-depressant prescription).</p> <p>Results</p> <p>Analyses were based on 2,005 (90.1%) individuals (mean age 70.8 years). Of 576 (28.7%) with probable depression (MH score < 60/100), 42.5% experienced one or more MH-related physician visits during follow-up. The likelihood of a physician visit was associated with sex (adjusted OR women vs. men = 5.87, p = 0.005) and MH score (adjusted OR per 10-point decrease in MH score = 1.63, p = 0.003). Among those aged 65+, 56.7% with probable depression received <it>any </it>MH care. The likelihood of receiving <it>any </it>MH care exhibited a significant interaction between MH score and self-reported health status (p = 0.0009); with good general health, worsening MH was associated with increased likelihood of MH care; as general health declined, this effect was attenuated.</p> <p>Conclusions</p> <p>Among older adults with painful OA, more than one-quarter had depressed mood, but almost half received no mental health care, suggesting a care gap.</p

Evolutional and clinical implications of the epigenetic regulation of protein glycosylation

Protein N glycosylation is an ancient posttranslational modification that enriches protein structure and function. The addition of one or more complex oligosaccharides (glycans) to the backbones of the majority of eukaryotic proteins makes the glycoproteome several orders of magnitude more complex than the proteome itself. Contrary to polypeptides, which are defined by a sequence of nucleotides in the corresponding genes, glycan parts of glycoproteins are synthesized by the activity of hundreds of factors forming a complex dynamic network. These are defined by both the DNA sequence and the modes of regulating gene expression levels of all the genes involved in N glycosylation. Due to the absence of a direct genetic template, glycans are particularly versatile and apparently a large part of human variation derives from differences in protein glycosylation. However, composition of the individual glycome is temporally very constant, indicating the existence of stable regulatory mechanisms. Studies of epigenetic mechanisms involved in protein glycosylation are still scarce, but the results suggest that they might not only be important for the maintenance of a particular glycophenotype through cell division and potentially across generations but also for the introduction of changes during the adaptive evolution

Intracellular iron uptake is favored in Hfe-KO mouse primary chondrocytes mimicking an osteoarthritis-related phenotype

HFE-hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE-hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe-KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild-type (wt) mice. Our data provide evidence that both wt- and Hfe-KO-derived chondrocytes, when exposed to 50 mu M iron, develop characteristics of an OA-related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe-KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 mu M iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex-determining region Y)-box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA-related phenotype.European Regional Development FundEuropean Union (EU) [EMBRC.PT Alg-01-0145-FEDER-022121, Norte-01-0145-FEDER-000012]Fundacao para a Ciencia e a TecnologiaPortuguese Foundation for Science and Technology [SFRH/BD/77056/2011]Portuguese Foundation for Science and TechnologyPortuguese Foundation for Science and TechnologyPortuguese Science and Technology FoundationPortuguese Foundation for Science and Technologyinfo:eu-repo/semantics/publishedVersio

MRI and 2D-CSI MR spectroscopy of the brain in the evaluation of patients with acute onset of neuropsychiatric systemic lupus erythematosus

MRI and 2D-CSI spectroscopy were performed in eight patients with systemic lupus erythematosus who presented with acute onset of neuropsychiatric lupus (NP-SLE), and in seven normal controls to evaluate for differences in metabolic peaks and metabolic ratios between the two groups. Also, the interval change of the metabolic peaks and their ratios during treatment in the NP-SLE patient group was evaluated. Metabolic peaks for N -acetyl-aspartate (NAA), choline (Cho), creatine (Cr), and lactate/lipids (LL) and their ratios (NAA/Cr, NAA/Cho, Cho/Cr, LL/Cr) were determined at initial presentation and 3 and 6 months later. In the eight lupus patients compared to the seven normal controls, NAA/Cho ratios were lower at presentation (1.05 vs 1.25; p  = 0.004) and decreased even further at the three month follow-up (0.92 vs 1.05; p  = 0.008). In contrast, both Cho/Cr (1.42 vs 1.26; p  = 0.026) and LL/Cr ratios (0.26 vs 0.19; p  = 0.002) were higher in the lupus patients at presentation compared to the controls and did not significantly change at three and six months follow-up. The NAA/Cr ratios were lower in the lupus patients compared to the controls at presentation but the difference was not statistically significant. However, the mean NAA/Cr significantly decreased from the initial examination to the three month follow-up (1.42 vs 1.32; p  = 0.049) but did not significantly change from the three to the six month follow-up examinations. The NAA/Cr, Cho/Cr, and NAA/Cho ratios varied significantly ( p  < 0.05, p  < 0.05, p  < 0.05, respectively) between the 17 different locations measured in the brain in all eight patients and seven controls. Both the NAA/Cr ratios and the Cho/Cr ratios were also significantly lower in the gray matter than in the white matter ( p  < 0.0001) in both patients and controls, whereas the LL/Cr and NAA/Cho ratios were not significantly different. In conclusion, 2D-CSI MR spectroscopy may be useful in the early detection of metabolic CNS changes in NP-SLE patients with acute onset of new neurological symptoms as well as in the follow-up after treatment to assess presence and changes in metabolic brain injury. However, although there are detectable differences between normal individuals and lupus patients it is currently unclear whether these relate to the acute episode. Future studies are needed comparing NP-SLE patients with active CNS involvement with those inactive disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46668/1/234_2005_Article_1371.pd

Supernova remnants: the X-ray perspective

Supernova remnants are beautiful astronomical objects that are also of high scientific interest, because they provide insights into supernova explosion mechanisms, and because they are the likely sources of Galactic cosmic rays. X-ray observations are an important means to study these objects.And in particular the advances made in X-ray imaging spectroscopy over the last two decades has greatly increased our knowledge about supernova remnants. It has made it possible to map the products of fresh nucleosynthesis, and resulted in the identification of regions near shock fronts that emit X-ray synchrotron radiation. In this text all the relevant aspects of X-ray emission from supernova remnants are reviewed and put into the context of supernova explosion properties and the physics and evolution of supernova remnants. The first half of this review has a more tutorial style and discusses the basics of supernova remnant physics and thermal and non-thermal X-ray emission. The second half offers a review of the recent advances.The topics addressed there are core collapse and thermonuclear supernova remnants, SN 1987A, mature supernova remnants, mixed-morphology remnants, including a discussion of the recent finding of overionization in some of them, and finally X-ray synchrotron radiation and its consequences for particle acceleration and magnetic fields.Comment: Published in Astronomy and Astrophysics Reviews. This version has 2 column-layout. 78 pages, 42 figures. This replaced version has some minor language edits and several references have been correcte