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  • 1
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    P. chrysosporium GH61D Structure and Dynamics [Computational Biology] (2013)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2013-05-04
    Description: Carbohydrate structures are modified and degraded in the biosphere by a myriad of mostly hydrolytic enzymes. Recently, lytic polysaccharide mono-oxygenases (LPMOs) were discovered as a new class of enzymes for cleavage of recalcitrant polysaccharides that instead employ an oxidative mechanism. LPMOs employ copper as the catalytic metal and are dependent on oxygen and reducing agents for activity. LPMOs are found in many fungi and bacteria, but to date no basidiomycete LPMO has been structurally characterized. Here we present the three-dimensional crystal structure of the basidiomycete Phanerochaete chrysosporium GH61D LPMO, and, for the first time, measure the product distribution of LPMO action on a lignocellulosic substrate. The structure reveals a copper-bound active site common to LPMOs, a collection of aromatic and polar residues near the binding surface that may be responsible for regio-selectivity, and substantial differences in loop structures near the binding face compared with other LPMO structures. The activity assays indicate that this LPMO primarily produces aldonic acids. Last, molecular simulations reveal conformational changes, including the binding of several regions to the cellulose surface, leading to alignment of three tyrosine residues on the binding face of the enzyme with individual cellulose chains, similar to what has been observed for family 1 carbohydrate-binding modules. A calculated potential energy surface for surface translation indicates that P. chrysosporium GH61D exhibits energy wells whose spacing seems adapted to the spacing of cellobiose units along a cellulose chain.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 2
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    Placental Expression of proBNP/NT-proBNP and Plasma Levels of NT-proBNP in Early- and Late-Onset Preeclampsia (2014)
    Oxford University Press
    Details
    Publication Date: 2014-08-14
    Description: BACKGROUND Levels of plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) are elevated in preeclampsia. In this study, the possibility that the placenta produces and releases proBNP/NT-proBNP was explored. Plasma levels of NT-proBNP in early- and late-onset preeclampsia were also measured. METHODS Placental proBNP mRNA in early-onset preeclampsia (n = 7), late-onset preeclampsia (n = 8), and controls of similar gestational age (n = 10) was assessed by quantitative real-time polymerase chain reaction. ProBNP/NT-proBNP protein was studied in placental samples with immunohistochemistry (n = 8) and tissue culture (n = 2). Plasma levels of NT-proBNP were measured in early-onset preeclampsia (n = 18), late-onset preeclampsia (n = 20), and relevant controls (n = 36). RESULTS Transcripts of proBNP mRNA were found in 20 out of 25 samples, there were no differences in expression between the groups. ProBNP/NT-proBNP protein was observed in maternal spiral arteries and in syncytiotrophoblasts in all placental samples. After placental tissue culture, there were measurable amounts of NT-proBNP in the culture media. Women with both early- (365 [14-9815] pg/ml) and late-onset preeclampsia (176 [33-2547] pg/ml) had higher levels of NT-proBNP than their controls ( P 〈 0.001). There was a tendency toward higher levels of NT-proBNP in women with early-onset preeclampsia than in women with late-onset preeclampsia ( P = 0.057). CONCLUSION The results indicate possible placental production and release of proBNP/NT-proBNP into the maternal circulation.
    Print ISSN: 0895-7061
    Electronic ISSN: 1879-1905
    Topics: Medicine
    Published by Oxford University Press
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  • 3
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    SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma (2014)
    Nature Publishing Group (NPG)
    In: Oncogene
    Details
    Publication Date: 2014-10-17
    Description: SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma Oncogene 33, 5006 (16 October 2014). doi:10.1038/onc.2013.443 Authors: M Trautmann, E Sievers, S Aretz, D Kindler, S Michels, N Friedrichs, M Renner, J Kirfel, S Steiner, S Huss, A Koch, R Penzel, O Larsson, A Kawai, S Tanaka, H Sonobe, A Waha, P Schirmacher, G Mechtersheimer, E Wardelmann, R Büttner & W Hartmann
    Keywords: Synovial sarcomaSYT-SSXβ-cateninWnt signaling pathwayPKF115-584CGP049090PKF118-310
    Print ISSN: 0950-9232
    Topics: Medicine
    Published by Nature Publishing Group (NPG)
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  • 4
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    Role of Dietary Fats in Modulating Cardiometabolic Risk During Moderate Weight Gain: A Randomized Double-Blind Overfeeding Trial (LIPOGAIN Study) [Preventive Cardiology] (2014)
    American Heart Association (AHA)
    Details
    Publication Date: 2014-10-25
    Description: Background Whether the type of dietary fat could alter cardiometabolic responses to a hypercaloric diet is unknown. In addition, subclinical cardiometabolic consequences of moderate weight gain require further study. Methods and Results In a 7-week, double-blind, parallel-group, randomized controlled trial, 39 healthy, lean individuals (mean age of 27±4) consumed muffins (51% of energy [%E] from fat and 44%E refined carbohydrates) providing 750 kcal/day added to their habitual diets. All muffins had identical contents, except for type of fat; sunflower oil rich in polyunsaturated fatty acids (PUFA diet) or palm oil rich in saturated fatty acids (SFA diet). Despite comparable weight gain in the 2 groups, total: high-density lipoprotein (HDL) cholesterol, low-density lipoprotein:HDL cholesterol, and apolipoprotein B:AI ratios decreased during the PUFA versus the SFA diet (–0.37±0.59 versus +0.07±0.29, –0.31±0.49 versus +0.05±0.28, and –0.07±0.11 versus +0.01±0.07, P =0.003, P =0.007, and P =0.01 for between-group differences), whereas no significant differences were observed for other cardiometabolic risk markers. In the whole group (ie, independently of fat type), body weight increased (+2.2%, P 〈0.001) together with increased plasma proinsulin (+21%, P =0.007), insulin (+17%, P =0.003), proprotein convertase subtilisin/kexin type 9, (+9%, P =0.008) fibroblast growth factor-21 (+31%, P =0.04), endothelial markers vascular cell adhesion molecule–1, intercellular adhesion molecule–1, and E-selectin (+9, +5, and +10%, respectively, P 〈0.01 for all), whereas nonesterified fatty acids decreased (–28%, P =0.001). Conclusions Excess energy from PUFA versus SFA reduces atherogenic lipoproteins. Modest weight gain in young individuals induces hyperproinsulinemia and increases biomarkers of endothelial dysfunction, effects that may be partly outweighed by the lipid-lowering effects of PUFA. Clinical Trial Registration URL: http://ClinicalTrials.gov . Unique identifier: NCT01427140.
    Electronic ISSN: 2047-9980
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 5
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    Serum Endostatin and Risk of Mortality in the Elderly: Findings From 2 Community-Based Cohorts [Clinical and Population Studies] (2013)
    American Heart Association (AHA)
    Details
    Publication Date: 2013-10-17
    Description: Objective— Experimental data imply that endostatin, a proteolytically cleaved fragment of collagen XVIII, could be involved in the development of cardiovascular disease and cancer. Prospective data concerning the relation between circulating endostatin and mortality are lacking. Accordingly, we aimed to study associations between circulating endostatin and mortality risk. Approach and Results— Serum endostatin was analyzed in 2 community-based cohorts: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 50%, n=931; mean age, 70 years; median follow-up, 7.9 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=748; mean age, 77 years; median follow-up, 9.7 years). During follow-up, 90 participants died in PIVUS (1.28/100 person-years at risk), and 417 participants died in ULSAM (6.7/100 person-years at risk). In multivariable Cox regression models adjusted for age and established cardiovascular risk factors, 1 SD higher ln(serum endostatin level) was associated with a hazard ratio of mortality of 1.39 and 95% confidence interval, 1.26 to 1.53, on average in both cohorts. In the ULSAM cohort, serum endostatin was also associated with cardiovascular mortality (177 deaths; hazard ratio per SD of ln[endostatin] 1.45, 95% confidence interval [1.25–1.71]) and cancer mortality (115 deaths; hazard ratio per SD of ln[endostatin] 1.35, 95% confidence interval [1.10–1.66]). Conclusions— High serum endostatin was associated with increased mortality risk in 2 independent community-based cohorts of the elderly. Our observational data support the importance of extracellular matrix remodeling in the underlying pathophysiology of cardiovascular disease and cancer.
    Print ISSN: 1079-5642
    Electronic ISSN: 1524-4636
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 6
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    Human prostasomes express glycolytic enzymes with capacity for ATP production (2013)
    The American Physiological Society (APS)
    Details
    Publication Date: 2013-03-16
    Description: Prostasomes are prostate-derived, exosome-like microvesicles that transmit signaling complexes between the acinar epithelial cells of the prostate and sperm cells. The vast majority of prostasomes have a diameter of 30–200 nm, and they are generally surrounded by a classical membrane bilayer. Using a selected proteomic approach, it became increasingly clear that prostasomes harbor distinct subsets of proteins that may be linked to adenosine triphosphate (ATP) metabolic turnover that in turn might be of importance in the role of prostasomes as auxiliary instruments in the fertilization process. Among the 21 proteins identified, most of the enzymes of anaerobic glycolysis were represented, and three of the glycolytic enzymes present are among the top 10 proteins found in most exosomes, once again linking prostasomes to the exosome family. Other prostasomal enzymes involved in ATP turnover were adenylate kinase, ATPase, 5'-nucleotidase, and hexose transporters. The identified enzymes in their prostasomal context were operational for ATP formation when supplied with substrates. The net ATP production was low due to a high prostasomal ATPase activity that could be partially inhibited by vanadate that was utilized to profile the ATP-forming ability of prostasomes. Glucose and fructose were equivalent as glycolytic substrates for prostasomal ATP formation, and the enzymes involved were apparently surface located on prostasomes, since an alternative substrate not being membrane permeable (glyceraldehyde 3-phosphate) was operative, too. There is no clear-cut function linked to this subset of prostasomal proteins, but some possible roles are discussed.
    Print ISSN: 0193-1849
    Electronic ISSN: 1522-1555
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 7
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    Urinary kidney injury molecule 1 and incidence of heart failure in elderly men (2013)
    Wiley-Blackwell
    Details
    Publication Date: 2013-03-23
    Description: Aims There is growing recognition of the clinical importance of cardiorenal syndrome—the bidirectional interplay between kidney and cardiac dysfunction. Yet, the role of kidney tubular damage in the development of heart failure is less studied. The objective of this study was to investigate whether urinary kidney injury molecule (KIM)-1, a specific marker of tubular damage, predisposes to an increased heart failure risk. Methods and results This was a community-based cohort study [Uppsala Longitudinal study of Adult Men (ULSAM)] of 565, 77-year-old men free from heart failure at baseline. Heart failure hospitalizations were used as outcome. During follow-up (median 8.0 years), 73 participants were hospitalized for heart failure. In models adjusted for cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, LDL/HDL ratio, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, LV hypertrophy, and prevalent cardiovascular disease) and markers of kidney dysfunction and damage [cystatin C-based glomerular filtration rate (GFR) and urinary albumin/creatinine ratio], a higher urinary KIM-1/creatinine ratio was associated with higher risk for heart failure (hazard ratio upper vs. lower tertile, 1.81; 95% confidence interval 1.01–3.29; P 〈 0.05). Participants with a combination of low GFR (〈60 mL/min/1.72 m 2 ) and high KIM-1/creatinine (〉128 ng/mmol) had a 3-fold increase in heart failure risk compared with participants with normal GFR and KIM-1 ( P 〈 0.001). Conclusion Our findings suggest that kidney tubular damage predisposes to an increased risk for heart failure in the community. Further studies are needed to clarify the causal role of KIM-1 in the development of heart failure, and to evaluate the clinical utility of urinary KIM-1 measurements.
    Print ISSN: 1388-9842
    Electronic ISSN: 1879-0844
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of The European Society of Cardiology.
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  • 8
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    Ferns acquired neochrome from hornworts [Evolution] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-05-07
    Description: Ferns are well known for their shade-dwelling habits. Their ability to thrive under low-light conditions has been linked to the evolution of a novel chimeric photoreceptor—neochrome—that fuses red-sensing phytochrome and blue-sensing phototropin modules into a single gene, thereby optimizing phototropic responses. Despite being implicated in facilitating the diversification of modern...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    Association Between Circulating Endostatin, Hypertension Duration, and Hypertensive Target-Organ Damage [Hypertensive Target Organ Damage] (2013)
    American Heart Association (AHA)
    Details
    Publication Date: 2013-11-14
    Description: Our aim is to study associations between circulating endostatin, hypertension duration, and hypertensive target-organ damage. Long-term hypertension induces cardiovascular and renal remodeling. Circulating endostatin, a biologically active derivate of collagen XVIII, has been suggested to be a relevant marker for extracellular matrix turnover and remodeling in various diseases. However, the role of endostatin in hypertension and hypertensive target-organ damage is unclear. Serum endostatin was measured in 2 independent community-based cohorts: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 51%; n=812; mean age, 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=785; mean age, 77.6 years). Retrospective data on blood pressure measurements and antihypertensive medication (PIVUS 〉5 years, ULSAM 〉27 years), and cross-sectional data on echocardiographic left ventricular mass, endothelial function (endothelium-dependent vasodilation assessed by the invasive forearm model), and urinary albumin/creatinine ratio were available. In PIVUS, participants with ≥5 years of history of hypertension portrayed 0.42 SD (95% confidence interval, 0.23–0.61; P 〈0.001) higher serum endostatin, compared with that of normotensives. This association was replicated in ULSAM, in which participants with 27 years hypertension duration had the highest endostatin (0.57 SD higher; 95% confidence interval, 0.35–0.80; P 〈0.001). In addition, higher endostatin was associated with higher left ventricular mass, worsened endothelial function, and higher urinary albumin/creatinine ratio ( P 〈0.03 for all) in participants with prevalent hypertension. Circulating endostatin is associated with the duration of hypertension, and vascular, myocardial, and renal indices of hypertensive target-organ damage. Further studies are warranted to assess the prognostic role of endostatin in individuals with hypertension.
    Print ISSN: 0194-911X
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 10
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    Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer [Medical Sciences] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-05-25
    Description: Prostasomes are microvesicles (mean diameter, 150 nm) that are produced and secreted by normal and malignant prostate acinar cells. It has been hypothesized that invasive growth of malignant prostate cells may cause these microvesicles, normally released into seminal fluid, to appear in interstitial space and therewith into peripheral circulation. The suitability of prostasomes as blood biomarkers in patients with prostate cancer was tested by using an expanded variant of the proximity ligation assay (PLA). We developed an extremely sensitive and specific assay (4PLA) for detection of complex target structures such as microvesicles in which the target is first captured via an immobilized antibody and subsequently detected by using four other antibodies with attached DNA strands. The requirement for coincident binding by five antibodies to generate an amplifiable reporter results in both increased specificity and sensitivity. The assay successfully detected significantly elevated levels of prostasomes in blood samples from patients with prostate cancer before radical prostatectomy, compared with controls and men with benign biopsy results. The medians for prostasome levels in blood plasma of patients with prostate cancer were 2.5 to sevenfold higher compared with control samples in two independent studies, and the assay also distinguished patients with high and medium prostatectomy Gleason scores (8/9 and 7, respectively) from those with low score (≤6), thus reflecting disease aggressiveness. This approach that enables detection of prostasomes in peripheral blood may be useful for early diagnosis and assessment of prognosis in organ-confined prostate cancer.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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