iAt Book Club: The Benedict Option

This submission marks iAt\u27s first book club series featuring the book, The Benedict Option: A Strategy for Christians in a Post-Christian Nation, by Rod Dreher. Various voices have contributed to the series as they interacted with one another and responded to the book. Series contributors are Donald Roth, Scott Culpepper, Gustavo Maya, Erin Olson, and Robert Lancaster. Access publisher\u27s site and additional readers\u27 comments: http://inallthings.org/tag/book-club

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies.

Canonical Wnt signaling is an osteo-inductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signaling and thus inhibits osteogenesis. To examine a potential osteo-inhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in pediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumor periphery and _in vitro_ Dkk-1 and RANKL are co-expressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduces osteogenesis by human mesenchymal cells and by immuno-depletion of Dkk-1, or by adding a GSK3[beta] inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumors was similar to the human tumor biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in osteosarcoma. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumor probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immuno-depletion of Dkk-1 or administration of GSK3[beta] inhibitors could represent an adjunct therapy for this disease

Operation of rain gauge and ground-water monitoring networks for the Imperial Valley Water Authority, year six: September 1997 - August 1998

The Illinois State Water Survey (ISWS), under contract to the Imperial Valley Water Authority (IVWA), has operated a network of rain gauges in Mason and Tazewell Counties since August 1992. The ISWS also established a network of ground-water observation wells in the Mason-Tazewell area. The networks are located in the most heavily irrigated region of the state. Ground water in various aquifers are the major source of the irrigation and domestic water supplies in the region. Recent extreme weather events (e.g., the drought of 1988 and the great flood of 1993) resulted in large fluctuations of the ground-water levels in the Imperial Valley area. The purpose of the rain gauge network and the ground-water observation well network is to collect a long-term series of data to determine the rate of ground-water drawdown in dry periods and during the growing season, and the rate at which the aquifers recharge. Precipitation is recorded for each storm that traverses the Imperial Valley, and ground-water levels at the 13 observation wells are measured the first of each month. The database from these networks consists of 6 years of precipitation data and 4 years of ground-water observations. At the beginning of the ground-water observations in 1995, the water levels were at the highest in the four years of observation. These high ground-water levels were the result of the very wet 1992-1995 period when annual precipitation was above the 30-year normals at both Havana and Mason City. From September 1995-August 1997 precipitation in the region was below the 30-year normal. The 1997-1998 observation year had rainfall above the 30-year normal. Ground-water levels in the observation wells mirrored these rainfall patterns, showing a general downward trend during the dry years and a recovery in the wet 1997-1998 year. Seasonal increases in the ground-water levels were observed at most wells during the late spring and early summer, followed by decreases in August-November ground water levels. Analysis indicates that the ground-water levels are affected by both the precipitation in the Imperial Valley area and the Illinois River stages. The observation wells closest to the Illinois River show an increase in water levels whenever the river stage is high. Generally, the water levels in the wells correlate best with precipitation and Illinois River stages one to two months before the water levels are measured, i.e., the June ground-water levels are most highly correlated with the Illinois River stage or precipitation that occurs in either April or May. The analyses conducted indicate the need for continued operation of both networks due to inconsistencies associated with ground-water levels, precipitation, and the Illinois River stage. For instance, the Mason-Tazwell observation well number 2 (MTOW-2) is located near the center of Mason County well away from the Illinois River, but it has an equal correlation with the Illinois River stage and the precipitation in the area. Additional analysis needs to be undertaken to explain this unusual finding

Short Communication: Analysis of Minor Populations of Human Immunodeficiency Virus by Primer Identification and Insertion-Deletion and Carry Forward Correction Pipelines

Accurate analysis of minor populations of drug-resistant HIV requires analysis of a sufficient number of viral templates. We assessed the effect of experimental conditions on the analysis of HIV pol 454 pyrosequences generated from plasma using (1) the ‘‘Insertion-deletion (indel) and Carry Forward Correction’’ (ICC) pipeline, which clusters sequence reads using a nonsubstitution approach and can correct for indels and carry forward errors, and (2) the ‘‘Primer Identification (ID)’’ method, which facilitates construction of a consensus sequence to correct for sequencing errors and allelic skewing. The Primer ID and ICC methods produced similar estimates of viral diversity, but differed in the number of sequence variants generated. Sequence preparation for ICC was comparably simple, but was limited by an inability to assess the number of templates analyzed and allelic skewing. The more costly Primer ID method corrected for allelic skewing and provided the number of viral templates analyzed, which revealed that amplifiable HIV templates varied across specimens and did not correlate with clinical viral load. This latter observation highlights the value of the Primer ID method, which by determining the number of templates amplified, enables more accurate assessment of minority species in the virus population, which may be relevant to prescribing effective antiretroviral therapy

Metastatic MTLn3 and non-metastatic MTC adenocarcinoma cells can be differentiated by Pseudomonas aeruginosa

Cancer patients are known to be highly susceptible to Pseudomonas aeruginosa (Pa) infection, but it remains unknown whether alterations at the tumor cell level can contribute to infection. This study explored how cellular changes associated with tumor metastasis influence Pa infection using highly metastatic MTLn3 cells and non-metastatic MTC cells as cell culture models. MTLn3 cells were found to be more sensitive to Pa infection than MTC cells based on increased translocation of the type III secretion effector, ExoS, into MTLn3 cells. Subsequent studies found that higher levels of ExoS translocation into MTLn3 cells related to Pa entry and secretion of ExoS within MTLn3 cells, rather than conventional ExoS translocation by external Pa. ExoS includes both Rho GTPase activating protein (GAP) and ADP-ribosyltransferase (ADPRT) enzyme activities, and differences in MTLn3 and MTC cell responsiveness to ExoS were found to relate to the targeting of ExoS-GAP activity to Rho GTPases. MTLn3 cell migration is mediated by RhoA activation at the leading edge, and inhibition of RhoA activity decreased ExoS translocation into MTLn3 cells to levels similar to those of MTC cells. The ability of Pa to be internalized and transfer ExoS more efficiently in association with Rho activation during tumor metastasis confirms that alterations in cell migration that occur in conjunction with tumor metastasis contribute to Pa infection in cancer patients. This study also raises the possibility that Pa might serve as a biological tool for dissecting or detecting cellular alterations associated with tumor metastasis

Role of hypoxia inducible factor-1α (HIF-1α) in innate defense against uropathogenic Escherichia coli infection

Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTI) affecting approximately 150 million people worldwide. Here, we revealed the importance of transcriptional regulator hypoxia-inducible factor-1 α subunit (HIF-1α) in innate defense against UPEC-mediated UTI. The effects of AKB-4924, a HIF-1α stabilizing agent, were studied using human uroepithelial cells (5637) and a murine UTI model. UPEC adherence and invasion were significantly reduced in 5637 cells when HIF-1α protein was allowed to accumulate. Uroepithelial cells treated with AKB-4924 also experienced reduced cell death and exfoliation upon UPEC challenge. In vivo, fewer UPEC were recovered from the urine, bladders and kidneys of mice treated transurethrally with AKB-4924, whereas increased bacteria were recovered from bladders of mice with a HIF-1α deletion. Bladders and kidneys of AKB-4924 treated mice developed less inflammation as evidenced by decreased pro-inflammatory cytokine release and neutrophil activity. AKB-4924 impairs infection in uroepithelial cells and bladders, and could be correlated with enhanced production of nitric oxide and antimicrobial peptides cathelicidin and β-defensin-2. We conclude that HIF-1α transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1α boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI

Cancer history and other personal factors affect quality of life in patients with hepatitis C

BACKGROUND: Although patients with chronic hepatitis C (CHC) have been found to have reduced quality of life, little is known about how other characteristics affect their quality of life. The purpose of this study was to investigate the effect of other characteristics, including history of cancer, on quality of life in patients with CHC. METHODS: One hundred forty patients from clinics at three hospitals in New York City completed a detailed epidemiologic interview about demographic and lifestyle characteristics and the SF-36 measuring health-related quality of life. We compared results from our patients to normative data using t-tests of differences between means. We used multivariate analyses to determine other personal and health-related factors associated with quality of life outcomes. RESULTS: Compared to normative data, these patients had reduced quality of life, particularly on physical functioning. The summary Physical Component Score (PCS) was 45.4 ± 10.6 and the Mental Component Score (MCS) was 48.2 ± 11.1, vs norms of 50 ± 10.0; p-values were <0.0001 and <0.05, respectively. In multivariate analyses, the PCS was significantly lower among those with cancer history, ≥ 2 other chronic conditions, less education, low physical activity, and higher alanine aminotransferase (ALT) levels. Cancer was more important for men, while other chronic conditions were more important for women. On the MCS, history of depression, low physical activity, alcohol use, and female gender were independently associated with poorer scores. CONCLUSION: Several health and lifestyle factors independently influence quality of life in CHC patients. Different factors are important for men and women

Banner News

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Computing and applying atomic regulons to understand gene expression and regulation

The Supplementary Material for this article can be found online at: http://journal.frontiersin.org/article/10.3389/fmicb.2016.01819/full#supplementary-materialUnderstanding gene function and regulation is essential for the interpretation prediction and ultimate design of cell responses to changes in the environment. An important step toward meeting the challenge of understanding gene function and regulation is the identification of sets of genes that are always co-expressed. These gene sets Atomic Regulons ARs represent fundamental units of function within a cell and could be used to associate genes of unknown function with cellular processes and to enable rational genetic engineering of cellular systems. Here we describe an approach for inferring ARs that leverages large-scale expression data sets gene context and functional relationships among genes. We computed ARs for Escherichia coli based on 907 gene expression experiments and compared our results with gene clusters produced by two prevalent data-driven methods: hierarchical clustering and k-means clustering. We compared ARs and purely data-driven gene clusters to the curated set of regulatory interactions for E. coli found in RegulonDB showing that ARs are more consistent with gold standard regulons than are data-driven gene clusters. We further examined the consistency of ARs and data-driven gene clusters in the context of gene interactions predicted by Context Likelihood of Relatedness CLR analysis finding that the ARs show better agreement with CLR predicted interactions. We determined the impact of increasing amounts of expression data on AR construction and find that while more data improve ARs it is not necessary to use the full set of gene expression experiments available for E. coli to produce high quality ARs. In order to explore the conservation of co-regulated gene sets across different organisms we computed ARs for Shewanella oneidensis Pseudomonas aeruginosa Thermus thermophilus and Staphylococcus aureus each of which represents increasing degrees of phylogenetic distance from E. coli. Comparison of the organism-specific ARs showed that the consistency of AR gene membership correlates with phylogenetic distance but there is clear variability in the regulatory networks of closely related organisms. As large scale expression data sets become increasingly common for model and non-model organisms comparative analyses of atomic regulons will provide valuable insights into fundamental regulatory modules used across the bacterial domain.JF acknowledges funding from [SFRH/BD/70824/2010] of the FCT (Portuguese Foundation for Science and Technology) PhD program. CH and PW were supported by the National Science Foundation under grant number EFRI-MIKS-1137089. RT was supported by the Genomic Science Program (GSP), Office of Biological and Environmental Research (OBER), U.S. Department of Energy(DOE),and his work is a contribution of the Pacific North west National Laboratory (PNNL) Foundational Scientific Focus Area. This work was partially supported by an award from the National Science Foundation to MD, AB, NT, and RO (NSFABI-0850546). This work was also supported by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Service [Contract No. HHSN272201400027C]