Excessive Complement Activation Due to Genetic Haploinsufficiency of Regulators in Multiple Human Diseases

The complement system is an ancient and powerful form of innate immunity. The alternative pathway (AP), a positive feedback loop, is at the core of the complement system. Activating components and regulators of the AP are genetically implicated in atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). aHUS features kidney failure, and often affects young children, but may occur throughout life and can be precipitated by pregnancy. aHUS associated variants are extremely rare and are considered highly penetrant. At the opposite end of the spectrum, AMD affects the retina leading to loss of central vision with a late age of onset. Risk variants in AMD are common in the population and have smaller effect sizes. I endeavored to understand the role of rare variants of large effect, similar to those causative in aHUS, in common diseases involving the kidney, specifically preeclampsia and lupus nephritis. I also examined the role of such variants in AMD. Because thousands of people must be studied to assess the impact of rare variation, I developed novel approaches allowing these experiments to be done with 10- to 100-fold reductions in both cost and labor. aHUS-like variants are present in preeclampsia, a syndrome that affects pregnant women and shares multiple pathologic findings with aHUS. These variants are present in ~1% of preeclamptic individuals. Additionally, aHUS-like rare variants are found in severe AMD patients. A diversity of variants in factor H and factor I are enriched in AMD cases. Subsets of these alleles have high penetrance in families and defective function. To study the effect of unregulated AP activation in vivo I studied a mouse deficient for the ubiquitous membrane regulator of complement Crry. Embryos that lack Crry are not viable due to attack by the maternal AP early in development. Damage in this model is unrelated to traditional forms of complement-mediated inflammation such as neutrophil activation or anaphylatoxin signaling. The findings of this body of work are an important step forward in understanding the risk individuals have of the common diseases PE and AMD and has implications for how these patients could be treated

Birth Weight And Risk Of Pediatric Hodgkin Lymphoma: A Population-Based Record Linkage Study In California

Abstract Objective: To evaluate the relationship between birth weight and the risk of pediatric Hodgkin lymphoma (HL, age at diagnosis: 0-19 years). Method: We linked California statewide birth records from 1978-2009 and cancer diagnosis data from 1988-2011 to conduct a population-based case-control study with 1,216 cases and 4,485 controls (matched on birth month and year, sex, and race/ethnicity). Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) of pediatric HL overall and by age of diagnosis, controlling for other perinatal factors. Results: Compared to children with a normal birth weight (2500-3999 g), those who had a high birth weight (≥ 4000 g) had a significantly increased risk of pediatric HL overall (OR=1.23, 95% CI: 1.02-1.48). The magnitude of association was larger for subgroups of children whose age of diagnosis was 0-10 years (OR=1.56, 95% CI: 1.04-2.24) or 15-19 years (OR=1.43, 95% CI: 1.11-1.83), while no association was observed in 11-14 year olds. Compared to firstborn children, those who were third or higher in birth order had a significantly reduced risk of pediatric HL overall (OR=0.80, 95% CI: 0.67-0.95), and this association also varied by age of diagnosis. Conclusions: In this study with the largest number of pediatric HL cases, high birth weight was associated with an increased disease risk. The different findings by age of diagnosis regarding both birth weight and birth order underscore the importance to stratify pediatric HL by age at diagnosis in future etiological investigations

Litters of photosynthetically divergent grasses exhibit differential metabolic responses to warming and elevated CO\u3csub\u3e2\u3c/sub\u3e

Climatic stress such as warming would alter physiological pathways in plants leading to changes in tissue chemistry. Elevated CO2 could partly mitigate warming induced moisture stress, and the degree of this mitigation may vary with plant functional types. We studied the composition of structural and non-structural metabolites in senesced tissues of Bouteloua gracilis (C4) and Pascopyrum smithii (C3) at the Prairie Heating and CO2 Enrichment experiment, Wyoming, USA. We hypothesized that P. smithii and B. gracilis would respond to unfavorable global change factors by producing structural metabolites and osmoregulatory compounds that are necessary to combat stress. However, due to the inherent variation in the tolerance of their photosynthetic pathways to warming and CO2, we hypothesized that these species will exhibit differential response under different combinations of warming and CO2 conditions. Due to a lower thermo-tolerance of the C4 photosynthesis we expected B. gracilis to exhibit a greater metabolic response under warming with ambient CO2 (cT) and P. smithii to exhibit a similar response under warming combined with elevated CO2 (CT). Our hypothesis was supported by the differential response of structural compounds in these two species, where cT increased the content of lignin and cuticular-matrix in B. gracilis. In P. smithii a similar response was observed in plants exposed to CT, possibly due to the partial alleviation of moisture stress.With warming, the total cell-wall bound phenolic acids that cross link polysaccharides to lignins increased in B. gracilis and decreased in P. smithii, indicating a potentially adaptive response of C4 pathway to warming alone. Similarly, in B. gracilis, extractable polar metabolites such as sugars and phenolic acids increased with the main effect of warming. Conversely, in P. smithii, only sugars showed a higher abundance in plants exposed to warming treatments indicating that warming alone might be metabolically too disruptive for the C3 photosynthetic pathway. Here we show for the first time, that along with traditionally probed extractable metabolites, warming and elevated CO2 differentially influence the structural metabolites in litters of photosynthetically divergent grass species. If these unique metabolite responses occur in other species of similar functional types, this could potentially alter carbon cycling in grasslands due to the varying degradability of these litters

Litters of photosynthetically divergent grasses exhibit differential metabolic responses to warming and elevated CO\u3csub\u3e2\u3c/sub\u3e

Climatic stress such as warming would alter physiological pathways in plants leading to changes in tissue chemistry. Elevated CO2 could partly mitigate warming induced moisture stress, and the degree of this mitigation may vary with plant functional types. We studied the composition of structural and non-structural metabolites in senesced tissues of Bouteloua gracilis (C4) and Pascopyrum smithii (C3) at the Prairie Heating and CO2 Enrichment experiment, Wyoming, USA. We hypothesized that P. smithii and B. gracilis would respond to unfavorable global change factors by producing structural metabolites and osmoregulatory compounds that are necessary to combat stress. However, due to the inherent variation in the tolerance of their photosynthetic pathways to warming and CO2, we hypothesized that these species will exhibit differential response under different combinations of warming and CO2 conditions. Due to a lower thermo-tolerance of the C4 photosynthesis we expected B. gracilis to exhibit a greater metabolic response under warming with ambient CO2 (cT) and P. smithii to exhibit a similar response under warming combined with elevated CO2 (CT). Our hypothesis was supported by the differential response of structural compounds in these two species, where cT increased the content of lignin and cuticular-matrix in B. gracilis. In P. smithii a similar response was observed in plants exposed to CT, possibly due to the partial alleviation of moisture stress.With warming, the total cell-wall bound phenolic acids that cross link polysaccharides to lignins increased in B. gracilis and decreased in P. smithii, indicating a potentially adaptive response of C4 pathway to warming alone. Similarly, in B. gracilis, extractable polar metabolites such as sugars and phenolic acids increased with the main effect of warming. Conversely, in P. smithii, only sugars showed a higher abundance in plants exposed to warming treatments indicating that warming alone might be metabolically too disruptive for the C3 photosynthetic pathway. Here we show for the first time, that along with traditionally probed extractable metabolites, warming and elevated CO2 differentially influence the structural metabolites in litters of photosynthetically divergent grass species. If these unique metabolite responses occur in other species of similar functional types, this could potentially alter carbon cycling in grasslands due to the varying degradability of these litters

Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse

PROBLEM: Crry is a widely expressed type 1 transmembrane complement regulatory protein in rodents which protects self-tissue by downregulating C3 activation. Crry METHOD OF STUDY: We investigated the basis of Crry RESULTS: We narrowed the critical period of the complement effect from 6.5 to 8.5 days post-coitus (dpc), which is immediately after the conceptus is exposed to maternal blood. Deposition by 5.5 dpc of maternal C3b on the placental vasculature lacking Crry CONCLUSION: Our data are most consistent with the deposition of C3b being responsible for the failure of the allantois to fuse to the chorion leading to subsequent conceptus demise

Dynamics of cubic-tetragonal phase transition in KNbO3_3 perovskite

The low-energy part of the vibration spectrum in KNbO$_3$ was studied by cold neutron inelastic scattering in the cubic phase. In addition to acoustic phonons, we observe strong diffuse scattering, which consists of two components. The first one is quasi-static and has a temperature-independent intensity. The second component appears as quasi-elastic scattering in the neutron spectrum indicating a dynamic origin. From analysis of the inelastic data we conclude that the quasi-elastic component and the acoustic phonon are mutually coupled. The susceptibility associated with the quasi-elastic component grows as the temperature approaches T$_C$

Enhancing the Legacy of California's Marine Protected Areas through Bottom-Up Collaboration

California enacted the Marine Life Protection Act in 1999 to create a network of Marine Protected Areas (MPAs) along the California coast. Through an eight-year process that engaged stakeholders, scientists, and policymakers, 124 MPAs were designated. During implementation, a network of county level collaboratives was formed to ensure that MPA management continued the bottom-up engagement of a diverse set of stakeholders. These collaboratives, and the Collaborative Network that supports them, have been an integral part of MPA management ever since 2012. The Collaborative Network is an ongoing experiment in collaborative governance and has been recognized as a key element in management of the MPAs. Our project analyzes the fourteen collaboratives, the Collaborative Network, and the relationships between the collaboratives, the Collaborative Network, and the State in an attempt to delineate the benefits and challenges of this arrangement, and identify best practices of collaborative governance. Interviews with members of the collaboratives and with stakeholders inform case studies of each collaborative. A cross-case analysis allowed us to identify key lessons that can be disseminated to other organizations attempting similar effortMaster of ScienceSchool for Environment and SustainabilityUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/167367/1/378_CaliMPA_Project.pd

Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort

Jane Salmon and colleagues studied 250 pregnant patients with SLE and/or antiphospholipid antibodies and found an association of risk variants in complement regulatory proteins in patients who developed preeclampsia, as well as in preeclampsia patients lacking autoimmune disease

Data Linkages to Study Pharmaceutical Health Services Delivery: Three Applied Examples

Introduction The safe, effective, and efficient use of pharmaceutical health services is a critical area of public health and social policy. Implementation and monitoring studies often use single data sources but require diverse data elements pertaining to patients and health services. Linking multiple data sources may enable more comprehensive studies. Objectives and Approach The objective of this presentation is to describe three applied pharmaceutical health services projects in the United States that use data linkage to support program monitoring. A conceptual model was defined including the following key domains: (1) contextual determinants; (2) pharmacy service availability and coverage by payers; (3) receipt/use of services by patients; and (4) outcomes such as clinical outcomes, patient satisfaction and healthcare costs. Applied studies were selected to illustrate data linkage across different domains. For each study, we present the data sources used and the domains addressed by each data source. We also describe the linkage process. Results Study 1 assesses distance between patients and pharmacies in-network for health plans. It determined pharmacy address and patient ZIP code using several Medicare datasets and calculated driving distance using geocoding software. Study 2 measures if patients targeted for services receive an intervention designed to prevent adverse drug events and improve patient health outcomes while reducing healthcare costs. Targeted beneficiaries are determined using Medicare administrative data and delivery of services is assessed based on a custom-developed encounter data set, linked by beneficiary. Study 3 examines the association between prescription drug formulary design, medication use, and cost and health outcomes. For this, formulary data are obtained from a commercial source and utilization/outcomes data from commercial claims data. These datasets are linked by payer. Conclusion/Implications Many data sources are available for pharmaceutical health services research studies and linkage can be made at the patient, region, or payer level to support program monitoring and evaluation. Data linkage enables the inclusion of multiple domains, although multiple linkages and/or custom data may be needed for more complex studies

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia : a genetic and functional study

Objective To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. Design A case-control study. Setting Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. Population We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. Methods The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. Main outcome measures Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. Results The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. Conclusions Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. Tweetable abstract Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.Peer reviewe