Tamm-Horsfall glycoprotein binds IgG with high affinity

Tamm-Horsfall glycoprotein binds IgG with high affinity. Tamm-Horsfall protein (THP), a monomelic glycoprotein (Mr 80 to 100 kDa), is produced by the mammalian kidney's thick ascending limb of Henle cells and excreted into the urine. The function of THP is uncertain. Here we report that a high molecular weight contaminant in sheep THP (sTHP) preparations was identified as sheep IgG by its positive reaction with donkey anti-sheep IgG antibody and with protein G. To answer the question of whether sTHP and sheep IgG co-purified because of a physical interaction between the two proteins, an enzyme-linked immunosorbent assay (ELISA) using immobilized sTHP and soluble sheep IgG was performed. Analysis of the ELISA data identified the presence of two sets of binding sites: a high affinity site (Kd 10-12 to 10-13 M) and a lower affinity site (Kd 10-10 to 10-11 M). The ELISA detected a similar high affinity interaction between human THP (hTHP) and human IgG. The binding of sheep IgG to immobilized sTHP was inhibited by soluble sTHP. These observations suggest an additional factor to be considered in studies addressing THP's potential immuno-regulatory function

The Opportunistic Transmission of Wireless Worms between Mobile Devices

The ubiquity of portable wireless-enabled computing and communications devices has stimulated the emergence of malicious codes (wireless worms) that are capable of spreading between spatially proximal devices. The potential exists for worms to be opportunistically transmitted between devices as they move around, so human mobility patterns will have an impact on epidemic spread. The scenario we address in this paper is proximity attacks from fleetingly in-contact wireless devices with short-range communication range, such as Bluetooth-enabled smart phones. An individual-based model of mobile devices is introduced and the effect of population characteristics and device behaviour on the outbreak dynamics is investigated. We show through extensive simulations that in the above scenario the resulting mass-action epidemic models remain applicable provided the contact rate is derived consistently from the underlying mobility model. The model gives useful analytical expressions against which more refined simulations of worm spread can be developed and tested.Comment: Submitted for publicatio

Metabolic syndrome and 10-year cardiovascular disease risk in the Hoorn study

BACKGROUND: Different definitions of the metabolic syndrome have been proposed. Their value in a clinical setting to assess cardiovascular disease (CVD) risk is still unclear. We compared the definitions proposed by the National Cholesterol Education Program Adult Treatment Panel III (NCEP), World Health Organization (WHO), European Group for the Study of Insulin Resistance (EGIR), and American College of Endocrinology (ACE) with respect to the prevalence of the metabolic syndrome and the association with 10-year risk of fatal and nonfatal CVD. METHODS AND RESULTS: The Hoorn Study is a population-based cohort study. The present study population comprised 615 men and 749 women aged 50 to 75 years and without diabetes or a history of CVD at baseline in 1989 to 1990. The prevalence of the metabolic syndrome at baseline ranged from 17% to 32%. The NCEP definition was associated with about a 2-fold increase in age-adjusted risk of fatal CVD in men and nonfatal CVD in women. For the WHO, EGIR, and ACE definitions, these hazard ratios were slightly lower. Risk increased with the number of risk factors. Elevated insulin levels were more prevalent in subjects with multiple risk factors, but metabolic syndrome definitions including elevated insulin level were not more strongly associated with risk. CONCLUSIONS: The metabolic syndrome, however defined, is associated with an approximate 2-fold increased risk of incident cardiovascular morbidity and mortality in a European population. In clinical practice, a more informative assessment can be obtained by taking into account the number of individual risk factor

Affective Determinants of Physical Activity: A Conceptual Framework and Narrative Review

The literature on affective determinants of physical activity (PA) is growing rapidly. The present paper aims to provide greater clarity regarding the definition and distinctions among the various affect-related constructs that have been examined in relation to PA. Affective constructs are organized according to the Affect and Health Behavior Framework (AHBF), including: (1) affective response (e.g., how one feels in response to PA behavior) to PA; (2) incidental affect (e.g., how one feels throughout the day, unrelated to the target behavior); (3) affect processing (e.g., affective associations, implicit attitudes, remembered affect, anticipated affective response, and affective judgments); and (4) affectively charged motivational states (e.g., intrinsic motivation, fear, and hedonic motivation). After defining each category of affective construct, we provide examples of relevant research showing how each construct may relate to PA behavior. We conclude each section with a discussion of future directions for research

Omada: robust clustering of transcriptomes through multiple testing

Background Cohort studies increasingly collect biosamples for molecular profiling and are observing molecular heterogeneity. High-throughput RNA sequencing is providing large datasets capable of reflecting disease mechanisms. Clustering approaches have produced a number of tools to help dissect complex heterogeneous datasets, but selecting the appropriate method and parameters to perform exploratory clustering analysis of transcriptomic data requires deep understanding of machine learning and extensive computational experimentation. Tools that assist with such decisions without prior field knowledge are nonexistent. To address this, we have developed Omada, a suite of tools aiming to automate these processes and make robust unsupervised clustering of transcriptomic data more accessible through automated machine learning–based functions. Findings The efficiency of each tool was tested with 7 datasets characterized by different expression signal strengths to capture a wide spectrum of RNA expression datasets. Our toolkit’s decisions reflected the real number of stable partitions in datasets where the subgroups are discernible. Within datasets with less clear biological distinctions, our tools either formed stable subgroups with different expression profiles and robust clinical associations or revealed signs of problematic data such as biased measurements. Conclusions In conclusion, Omada successfully automates the robust unsupervised clustering of transcriptomic data, making advanced analysis accessible and reliable even for those without extensive machine learning expertise. Implementation of Omada is available at http://bioconductor.org/packages/omada/

ADAMTS -1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are a recently described group of metalloproteinases. The substrates degraded by ADAMTS-1, -4 and -5 suggests that they play a role in turnover of extracellular matrix in the central nervous system (CNS). ADAMTS-1 is also known to exhibit anti-angiogenic activity. Their main endogenous inhibitor is tissue inhibitor of metalloproteinases (TIMP)-3. The present study was designed to investigate ADAMTS-1, -4 and -5 and TIMP-3 expression after experimental cerebral ischaemia and to examine whether cytokines known to be up-regulated in stroke could alter their expression by astrocytes in vitro. Focal cerebral ischaemia was induced by transient middle cerebral artery occlusion in the rat using the filament method. Our results demonstrate a significant increase in expression of ADAMTS-1 and -4 in the occluded hemisphere but no significant change in TIMP-3. This was accompanied by an increase in mRNA levels for interleukin (IL)-1, IL-1 receptor antagonist (IL-1ra) and tumour necrosis factor (TNF). ADAMTS-4 mRNA and protein was up-regulated by TNF in primary human astrocyte cultures. The increased ADAMTS-1 and -4 in experimental stroke, together with no change in TIMP-3, may promote ECM breakdown after stroke, enabling infiltration of inflammatory cells and contribute to brain injury. In vitro studies suggest that the in vivo modulation of ADAMTS-1 and -4 may be controlled in part by TNF.</p

Post-tectonic landscape evolution in NE Iberia using staircase terraces: Combined effects of uplift and climate

© 2017 Elsevier B.V.River incision into bedrock resulting from the combined effects of tectonic uplift and climate governs long-term regional landscape evolution. We determined spatial and temporal patterns of post-orogenic stream incision from a sequence of well-preserved staircase terraces developed over the last 1 Ma in the Central Pyrenees and its southern foreland Ebro basin (NE Spain). Extensive remnants of ten vertically separated terraces (Qt1 to Qt10, from oldest to youngest) were mapped along 170 km of the Cinca River valley, transverse to the Pyrenean mountain belt. Multiple outcrops appear in the upper reach of the valley (Ainsa sector, 50 km from headwaters) as well as in the lower reach (Albalate sector, 125 km from headwaters). Fluvial incision into bedrock was calculated using (i) differentially corrected GPS measurements of the altitude of straths and (ii) numerical dating of alluvial sediments from the lower terraces (Qt5 to Qt9) by Optically Stimulated Luminescence, previously reported by Lewis et al. (2009), and supplemented with new dates for the upper terraces (Qt1, Qt2 and Qt3) based on paleomagnetism and supported by soil development. Considering altitude differences and the elapsed time between successive well preserved terrace couples (Qt3–Qt7, Qt7–Qt9 and Qt9-Active channel), mean bedrock incision rates ranged from 0.76 to 0.38 m ka− 1, at the upper reach of the valley (Ainsa section), and from 0.61 to 0.20 m ka− 1, at the lower reach (Albalate section). River incision along the valley produced vertically separated, near-parallel longitudinal terrace profiles evidencing a rapid near-uniform regional uplift as response to (i) the tectonic lithospheric thickening in NE Iberia and (ii) the erosional download rebound related to the Ebro basin exorheism. Moreover, a subtle upstream divergence of strath profiles may have been a consequence of an increase in uplift rate toward the head of the valley. Additionally, incision rates changed over time as indicate results from the lower reach (Albalate section); the maximum rate was 1.48 m ka− 1 between Qt7 (61 ka) and Qt8 (47 ka), and the minimum rate was 0.11 m ka− 1 between Qt3 (401 ka) and Qt5 (178 ka). The highest incision rates were produced after the Marine Isotope Stage 4 most likely in response to (i) an increased snowmelt discharge during the subsequent deglaciation related to the last maximum advance of glaciers in the southern Pyrenees, and (ii) a limited width of the valley after Qt7 formation, resulting from the deactivation of the westward river migration. Therefore, incision rates over the last 1 Ma in the Cinca River valley were basically controlled by near-uniform bedrock uplift, in the context of climate variability. The results reported in this study represent significant data on fluvial incision in NE Iberia, and provide an assessment of the regional post-tectonic landscape evolution

Plasma Metabolomics Implicate Modified Transfer RNAs and Altered Bioenergetics in the Outcome of Pulmonary Arterial Hypertension.

BACKGROUND: -Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. METHODS: -We conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry to (1) identify patients at high risk of early death, (2) identify patients who respond well to treatment and (3) provide novel molecular insights into disease pathogenesis. RESULTS: -53 circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy controls (n=121) following correction for multiple testing (p<7.3e-5) and confounding factors, including drug therapy, renal and hepatic impairment. A subset of 20/53 metabolites also discriminated PAH patients from disease controls (symptomatic patients without pulmonary hypertension, n=139). 62 metabolites were prognostic in PAH, with 36/62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), TCA cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan and polyamine metabolites and decreased levels of steroids, sphingomyelins and phosphatidylcholines distinguished patients from controls. The largest differences correlated with increased risk of death and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to healthy controls. CONCLUSIONS: -Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterisation of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients