Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation

Genetic testing has uncovered rare variants in complement proteins associated with thrombotic microangiopathy (TMA) and C3 glomerulopathy (C3G). Approximately 50% are classified as variants of uncertain significance (VUS). Clinical risk assessment of patients carrying a VUS remains challenging primarily due to a lack of functional information, especially in the context of multiple confounding factors in the setting of kidney transplantation. Our objective was to evaluate the clinicopathologic significance of genetic variants in TMA and C3G in a kidney transplant cohort. We used whole exome next-generation sequencing to analyze complement genes in 76 patients, comprising 60 patients with a TMA and 16 with C3G. Ten variants in complement factor H (CFH) were identified; of these, four were known to be pathogenic, one was likely benign and five were classified as a VUS (I372V, I453L, G918E, T956M, L1207I). Each VUS was subjected to a structural analysis and was recombinantly produced; if expressed, its function was then characterized relative to the wild-type (WT) protein. Our data indicate that I372V, I453L, and G918E were deleterious while T956M and L1207I demonstrated normal functional activity. Four common polymorphisms in CFH (E936D, N1050Y, I1059T, Q1143E) were also characterized. We also assessed a family with a pathogenic variant in membrane cofactor protein (MCP) in addition to CFH with a unique clinical presentation featuring valvular dysfunction. Our analyses helped to determine disease etiology and defined the recurrence risk after kidney transplant, thereby facilitating clinical decision making for our patients. This work further illustrates the limitations of the prediction models and highlights the importance of conducting functional analysis of genetic variants particularly in a complex clinicopathologic scenario such as kidney transplantation

Aminopyralid + Metsulfuron-Methyl for Cost-Effective Control of Hard to Kill Pasture Weeds

This paper summarises research trials conducted from 2010 to 2013 to determine speed of brownout and efficacy of an aminopyralid + metsulfuron-methyl herbicide product in pastures compared to metsulfuron alone and current commercial standards

Absence of neutralizing antibodies against influenza A/H5N1 virus among children in Kamphaeng Phet, Thailand

Background: Influenza A/H5N1 actively circulated in Kamphaeng Phet (KPP), Thailand from 2004 to 2006. A prospective longitudinal cohort study of influenza virus infection in 800 adults conducted during 2008–2010 in KPP suggested that subclinical or mild H5N1 infections had occurred among this adult cohort. However, this study was conducted after the peak of H5N1 activity in KPP. Coincidentally, banked serum samples were available from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses from 2004 to 2007 and lived in the same district of KPP as the adult cohort. Objectives: We sought to investigate whether subclinical or mild H5N1 infections had occurred among KPP residents during the peak of H5N1 activity from 2004 to 2006. Study design: H5N1 microneutralization (MN) assay was performed on banked serum samples from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses in KPP. Annual blood samples collected from 2004 to 2006 from 251 children were selected based on the criteria that they lived in villages with documented H5N1 infection. Result: No H5N1 neutralizing antibodies were detected in 753 annual blood samples from 251 children. Conclusion: During 2004–2006, very few subclinical or mild H5N1 infections occurred in KPP. Elevated H5N1 MN titers found in the adult cohort in 2008 were likely due to cross-reactivity from other influenza virus subtypes highlighting the complexities in interpreting influenza serological data

Visual Analysis of Weblog Content

In recent years, one of the advances of the World Wide Web is social media and one of the fastest growing aspects of social media is the blogosphere. Blogs make content creation easy and are highly accessible through web pages and syndication. With their growing influence, a need has arisen to be able to monitor the opinions and insight revealed within their content. In this paper we describe a technical approach for analyzing the content of blog data using a visual analytic tool, IN-SPIRE, developed by Pacific Northwest National Laboratory. We highlight the capabilities of this tool that are particularly useful for information gathering from blog data

Stable isotopes can be used to infer the overwintering locations of prebreeding marine birds in the Canadian Arctic

Although assessments of winter carryover effects on fitness-related breeding parameters are vital for determining the links between environmental variation and fitness, direct methods of determining overwintering distributions (e.g., electronic tracking) can be expensive, limiting the number of individuals studied. Alternatively, stable isotope analysis in specific tissues can be used as an indirect means of determining individual overwintering areas of residency. Although increasingly used to infer the overwintering distributions of terrestrial birds, stable isotopes have been used less often to infer overwintering areas of marine birds. Using Arctic-breeding common eiders, we test the effectiveness of an integrated stable isotope approach (13-carbon, 15-nitrogen, and 2-hydrogen) to infer overwintering locations. Knowing the overwinter destinations of eiders from tracking studies at our study colony at East Bay Island, Nunavut, we sampled claw and blood tissues at two known overwintering locations, Nuuk, Greenland, and Newfoundland, Canada. These two locations yielded distinct tissue-specific isotopic profiles. We then compared the isotope profiles of tissues collected from eiders upon their arrival at our breeding colony, and used a k-means cluster analysis approach to match arriving eiders to an overwintering group. Samples from the claws of eiders were most effective for determining overwinter origin, due to this tissue\u27s slow growth rate relative to the 40-day turnover rate of blood. Despite taking an integrative approach using multiple isotopes, k-means cluster analysis was most effective when using 13-carbon alone to assign eiders to an overwintering group. Our research demonstrates that it is possible to use stable isotope analysis to assign an overwintering location to a marine bird. There are few examples of the effective use of this technique on a marine bird at this scale; we provide a framework for applying this technique to detect changes in the migration phenology of birds\u27 responses to rapid changes in the Arctic

Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation

Alternative (M2) macrophage activation driven through interleukin 4 receptor α (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of fatty acids to support this metabolic program has not been clear. We show that the uptake of triacylglycerol substrates via CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation (OXPHOS), enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth, and blocked protective responses against this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation

Detectability of gravitational wave events by spherical resonant-mass antennas

We have calculated signal-to-noise ratios for eight spherical resonant-mass antennas interacting with gravitational radiation from inspiralling and coalescing binary neutron stars and from the dynamical and secular bar-mode instability of a rapidly rotating star. We find that by using technology that could be available in the next several years, spherical antennas can detect neutron star inspiral and coalescence at a distance of 15 Mpc and the dynamical bar-mode instability at a distance of 2 Mpc.Comment: 39 pages, 4 EPS Figures, some additional SNRs for secular instabilities, some changes to LIGO SNRs, Appendix added on the asymptotic expansion of energy sensitivity, corrected supernova rates. Results available at http://www.physics.umd.edu/rgroups/gen_rel_exp/snr.html Submitted to Phys. Rev.

Uncovering the genomic basis of an extraordinary plant invasion

Invasive species are a key driver of the global biodiversity crisis, but the drivers of invasiveness, including the role of pathogens, remain debated. We investigated the genomic basis of invasiveness in Ambrosia artemisiifolia (common ragweed), introduced to Europe in the late 19th century, by resequencing 655 ragweed genomes, including 308 herbarium specimens collected up to 190 years ago. In invasive European populations, we found selection signatures in defense genes and lower prevalence of disease-inducing plant pathogens. Together with temporal changes in population structure associated with introgression from closely related Ambrosia species, escape from specific microbial enemies likely favored the plant's remarkable success as an invasive species.Peer reviewe

Brain arteriolosclerosis

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g. hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that include consideration of comorbid diseases, B-ASC is independently associated with impairments in global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability

Polymorphism of the CD36 Gene and Cardiovascular Risk Factors in Patients with Coronary Artery Disease Manifested at a Young Age

This study investigates potential associations between CD36 gene variants and the presence of risk factors in Caucasians with coronary artery disease (CAD) manifested at a young age. The study group consisted of 90 patients; the men were ≤ 50 years old and the women were ≤ 55 years old. Amplicons of exons 4 and 5 including fragments of introns were analyzed by DHPLC. Two polymorphisms were found: IVS3-6 T/C (rs3173798) and IVS4-10 G/A (rs3211892). The C allele of the IVS3-6 T/C polymorphism was associated with higher prevalence of obesity and diabetes, higher hsCRP, lower Lp(a) serum concentrations, and younger age at myocardial infarction. The A allele of the IVS4-10 G/A polymorphism was associated with older age of myocardial infarction and higher white blood cell count. The functional role of CD36 polymorphisms in CAD development needs further research