A Correlation between Protein Function and Ligand Binding Profiles

We report that proteins with the same function bind the same set of small molecules from a standardized chemical library. This observation led to a quantifiable and rapidly adaptable method for protein functional analysis using experimentally-derived ligand binding profiles. Ligand binding is measured using a high-throughput NMR ligand affinity screen with a structurally diverse chemical library. The method was demonstrated using a set of 19 proteins with a range of functions. A statistically significant similarity in ligand binding profiles was only observed between the two functionally identical albumins and between the five functionally similar amylases. This new approach is independent of sequence, structure or evolutionary information, and therefore, extends our ability to analyze and functionally annotate novel genes

Points and Pits: Archaeological Investigations in Minnesota’s Region 9, the Lake Superior Shore, Carlton, Cook, Lake, and St. Louis Counties, Minnesota

Duluth Archaeology Center Report No. 11-22. Duluth: Duluth Archeology Center.This report is essentially an archeological survey of northeastern Minnesota’s coastal region, for which little is known about prehistoric human occupation. The authors first conducted a literature review, then carried out field investigations at 34 sites in 2010. Most of the sites were already known, and only four new sites suggesting historic use or habitation were found, all in Jay Cooke State Park. The study focused on sites that were not far from water. The report describes archeological and GIS methods used to select and explore the sites. The authors conclude that some progress has been made in contributing to a historical database for the region, but that much more remains to be discovered about prehistoric occupation on the Lake Superior shoreline. Key sections of the report are extracted and reproduced below. Summary: "This project was designed to add to our knowledge of Region 9, which was poorly known as a result of relatively few previously recorded. Four objectives were stated for the project to be conducted in three tasks. A summary of what is currently known about the prehistoric occupation of the region was the first task. Both literature and collections review were specifically included as sources. Updating the State Archaeologist site files for known sites and locating new sites was the second task, including both checking on sites reported by private collectors and new survey. The fourth objective was to develop a narrative predictive model of prehistoric site location for agency managers prehistoric archaeological sites (a total of 34). The field survey for new sites, most of which had to be conducted in fall 2010 before the ground froze, focused on a GIS compilation of several environmental factors previously thought to be important predictors of prehistoric site locations: distance to water (50 and 100 m) and slope (5%, 7%, 10%). Where possible, information on shoreline features from glacial lakes was also incorporated. Factors of access and land ownership (public lands preferable) were also compiled. Specific locations were then selected by the field archaeologist, drawing on decades of experience. Survey followed standard procedures, mainly shovel testing but pedestrian walkover where possible. Only four new archaeological sites were located, all in Jay Cooke State Park and all initially found by surface finds in Park trails. “Most of the areas selected for survey (County and City lands in St. Louis County, Split Rock Lighthouse State Park in Lake County, Judge Magney State Park in Cook County) were either negative or untestable. Concurrently with preparation for new survey, informant reports of new sites were recorded and, where possible, field verified in fall 2010. The response from members of the local archaeological society was overwhelming; over three dozen leads were given, about half for prehistoric sites and half for historic sites that might have prehistoric components. Additional site leads were supplied from members of the general public who heard of the project from media releases or by word of mouth. Although some site leads were either natural items or outside the Region 9 boundary, several prehistoric sites were recorded from this source. The data from both sources suggest that sites in Region 9 do tend to correlate to water, both past and present; however, specific numerical values for environmental variables are not as productive as viewing topography in the field. Areas of low slope are also high potential but not all flat area near water have site materials. Areas of low to no potential would include areas of steep slope (but not all area greater than 10% slope), water saturation (both permanent and seasonal), and/or areas at far distances from water (although quantitative measures are not firm). Much more research needs to be conducted to understand the pre-Contact occupation of the region, as well as develop a better predictive model of site location.

Interleukin-10 Overexpression Promotes Fas-Ligand-Dependent Chronic Macrophage-Mediated Demyelinating Polyneuropathy

BACKGROUND:Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. PRINCIPAL FINDINGS:Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death. SIGNIFICANCE:These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome

Bridging Alone: Religious Conservatism, Marital Homogamy, and Voluntary Association Membership

This study characterizes social insularity of religiously conservative American married couples by examining patterns of voluntary associationmembership. Constructing a dataset of 3938 marital dyads from the second wave of the National Survey of Families and Households, the author investigates whether conservative religious homogamy encourages membership in religious voluntary groups and discourages membership in secular voluntary groups. Results indicate that couples’ shared affiliation with conservative denominations, paired with beliefs in biblical authority and inerrancy, increases the likelihood of religious group membership for husbands and wives and reduces the likelihood of secular group membership for wives, but not for husbands. The social insularity of conservative religious groups appears to be reinforced by homogamy—particularly by wives who share faith with husbands

Searching the protein structure database for ligand-binding site similarities using CPASS v.2

<p>Abstract</p> <p>Background</p> <p>A recent analysis of protein sequences deposited in the NCBI RefSeq database indicates that ~8.5 million protein sequences are encoded in prokaryotic and eukaryotic genomes, where ~30% are explicitly annotated as "hypothetical" or "uncharacterized" protein. Our Comparison of Protein Active-Site Structures (CPASS v.2) database and software compares the sequence and structural characteristics of experimentally determined ligand binding sites to infer a functional relationship in the absence of global sequence or structure similarity. CPASS is an important component of our Functional Annotation Screening Technology by NMR (FAST-NMR) protocol and has been successfully applied to aid the annotation of a number of proteins of unknown function.</p> <p>Findings</p> <p>We report a major upgrade to our CPASS software and database that significantly improves its broad utility. CPASS v.2 is designed with a layered architecture to increase flexibility and portability that also enables job distribution over the Open Science Grid (OSG) to increase speed. Similarly, the CPASS interface was enhanced to provide more user flexibility in submitting a CPASS query. CPASS v.2 now allows for both automatic and manual definition of ligand-binding sites and permits pair-wise, one versus all, one versus list, or list versus list comparisons. Solvent accessible surface area, ligand root-mean square difference, and Cβ distances have been incorporated into the CPASS similarity function to improve the quality of the results. The CPASS database has also been updated.</p> <p>Conclusions</p> <p>CPASS v.2 is more than an order of magnitude faster than the original implementation, and allows for multiple simultaneous job submissions. Similarly, the CPASS database of ligand-defined binding sites has increased in size by ~ 38%, dramatically increasing the likelihood of a positive search result. The modification to the CPASS similarity function is effective in reducing CPASS similarity scores for false positives by ~30%, while leaving true positives unaffected. Importantly, receiver operating characteristics (ROC) curves demonstrate the high correlation between CPASS similarity scores and an accurate functional assignment. As indicated by distribution curves, scores ≥ 30% infer a functional similarity. Software URL: <url>http://cpass.unl.edu</url>.</p

Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes.

Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Rhodes Scholarships; doi: https://doi.org/10.13039/501100000697Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274Disclosing secondary findings (SF) from genome sequencing (GS) can alert carriers to disease risk. However, evidence around variant-disease association and consequences of disclosure for individuals and healthcare services is limited. We report on the feasibility of an approach to identification of SF in inherited cardiac conditions (ICC) genes in participants in a rare disease GS study, followed by targeted clinical evaluation. Qualitative methods were used to explore behavioural and psychosocial consequences of disclosure. ICC genes were analysed in genome sequence data from 7203 research participants; a two-stage approach was used to recruit genotype-blind variant carriers and matched controls. Cardiac-focused medical and family history collection and genetic counselling were followed by standard clinical tests, blinded to genotype. Pathogenic ICC variants were identified in 0.61% of individuals; 20 were eligible for the present study. Four variant carriers and seven non-carrier controls participated. One variant carrier had a family history of ICC and was clinically affected; a second was clinically unaffected and had no relevant family history. One variant, in two unrelated participants, was subsequently reclassified as being of uncertain significance. Analysis of qualitative data highlights participant satisfaction with approach, willingness to follow clinical recommendations, but variable outcomes of relatives' engagement with healthcare services. In conclusion, when offered access to SF, many people choose not to pursue them. For others, disclosure of ICC SF in a specialist setting is valued and of likely clinical utility, and can be expected to identify individuals with, and without a phenotype

The Rising Star-Formation Histories of Distant Galaxies and Implications for Gas Accretion with Time

Distant galaxies show correlations between their current star-formation rates (SFRs) and stellar masses, implying that their star-formation histories (SFHs) are highly similar. Moreover, observations show that the UV luminosities and stellar masses grow from z=8 to 3, implying that the SFRs increase with time. We compare the cosmologically averaged evolution in galaxies at 3 < z < 8 at constant comoving number density, n = 2 x 10^-4 Mpc^-3. This allows us to study the evolution of stellar mass and star formation in the galaxy predecessors and descendants in ways not possible using galaxies selected at constant stellar mass or SFR, quantities that evolve strongly in time. We show that the average SFH of these galaxies increase smoothly from z=8 to 3 as SFR ~ t^alpha with alpha = 1.7 +/- 0.2. This conflicts with assumptions that the SFR is either constant or declines exponentially in time. We show that the stellar mass growth in these galaxies is consistent with this derived SFH. This provides evidence that the slope of the high-mass end of the IMF is approximately Salpeter unless the duty cycle of star formation is much less than unity. We argue that these relations follow from gas accretion (either through accretion or delivered by mergers) coupled with galaxy disk growth under the assumption that the SFR depends on the local gas surface density. This predicts that gas fractions decrease from z=8 to 3 on average as f_gas ~ (1+z)^0.9 for galaxies with this number density. The implied galaxy gas accretion rates at z > 4 are as fast and may even exceed the SFR: this is the "gas accretion epoch". At z < 4 the SFR overtakes the implied gas accretion rate, indicating a period where galaxies consume gas faster than it is acquired. At z < 3, galaxies with this number density depart from these relations implying that star formation and gas accretion are slowed at later times.Comment: Accepted for publication in MNRAS. 13 pages, 7 figures. Comments welcome. Updated with MNRAS-accepted versio

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Challenge Accepted! a Critical Reflection on How to Perform a Health Survey Among University Students—An Example of the Healthy Campus Mainz Project

Background: Universities represent an important setting of everyday life for health promotion. The Healthy Campus Mainz project aims to develop an evidence-based and comprehensive student health management program covering physical, mental, and social health promotion. Hence, an initial health survey was performed in order to identify the students' health concerns and resources. Up until now, it remains unclear which topics to choose in a health survey among university students and which strategies can be recommended to receive an acceptable response rate or representative student sample within a university setting. The present paper contributes to the call for the present research topic “Public Health Promotion in University Students” by describing methods for health assessment. Therefore, the current paper aims to give an empirical example on how to perform a health survey among university students, focusing on (1) choosing topics for the survey and (2) methodological considerations of how to reach the target population.Methods: An online questionnaire including around 270 items was developed covering a comprehensive set of health topics. Participants were recruited via the university email. Mixed channels for survey promotion, such as lecture visits and social media, were used, accompanied by different monetary and non-monetary incentives. Descriptive analyses were performed to describe the sample.Results: A total of 5,006 participants (out of 31,213 registered students) viewed the first page of the questionnaire; of whom, 4,714 continued further. After a manual data cleaning according to the predefined criteria, the final sample was 4,351, demonstrating a response rate of 13.9%. Students from different study disciplines participated. However, some study disciplines showed a low participation rate, hence, making the results not free from some bias.Discussion: This survey is exceptional as it integrates a great variety of health aspects. The incentive strategy demonstrated promising results. Future research should try to improve target-group-specific recruitment strategies for the traditionally underrepresented groups, such as males and specific study disciplines. This would not only include advancing marketing strategies, but also refining the incentive strategy

2019 Scholars at Work Conference Program

Program for the 2019 Scholars at Work Conference at Minnesota State University, Mankato on March 29, 2019