Surface Ocean Biogeochemistry Regulates the Impact of Anthropogenic Aerosol Fe Deposition on the Cycling of Iron and Iron Isotopes in the North Pacific.

Distinctively-light isotopic signatures associated with Fe released from anthropogenic activity have been used to trace basin-scale impacts. However, this approach is complicated by the way Fe cycle processes modulate oceanic dissolved Fe (dFe) signatures (δ56Fediss) post deposition. Here we include dust, wildfire, and anthropogenic aerosol Fe deposition in a global ocean biogeochemical model with active Fe isotope cycling, to quantify how anthropogenic Fe impacts surface ocean dFe and δ56Fediss. Using the North Pacific as a natural laboratory, the response of dFe, δ56Fediss, and primary productivity are spatially and seasonally variable and do not simply follow the footprint of atmospheric deposition. Instead, the effect of anthropogenic Fe is regulated by the biogeochemical regime, specifically the degree of Fe limitation and rates of primary production. Overall, we find that while δ56Fediss does trace anthropogenic input, the response is muted by fractionation during phytoplankton uptake, but amplified by other isotopically-light Fe sources.

Associations of social cohesion and quality of life with objective and perceived built environments: a latent profile analysis among seniors.

BACKGROUND: Healthy aging requires support from local built and social environments. Using latent profile analysis, this study captured the multidimensionality of the built environment and examined relations between objective and perceived built environment profiles, neighborhood social cohesion and quality of life among seniors. METHODS: In total, 693 participants aged 66-97 were sampled from two US locales in 2005-2008 as part of the Senior Neighborhood Quality of Life Study (SNQLS). Perceived social cohesion and quality of life were assessed using validated surveys. Six objective (geographic information system (GIS)-based) and seven perceived built environment latent profiles generated in previous SNQLS publications were used for analyses. Mixed-effects models estimated social cohesion and quality of life separately as a function of the built environment profiles. RESULTS: More walkable and destination-rich perceived built environment profiles were associated with higher social cohesion and quality of life. Objective built environment profiles were not associated with social cohesion and only positively associated with quality of life in only one locale (Baltimore/DC). CONCLUSIONS: Latent profile analysis offered a comprehensive approach to assessing the built environment. Seniors who perceived their neighborhoods to be highly walkable and recreationally dense experienced higher neighborhood social cohesion and quality of life, which may set the stage for healthier aging.

Constraints on the Cycling of Iron Isotopes From a Global Ocean Model.

Although iron (Fe) is a key regulator of primary production over much of the ocean, many components of the marine iron cycle are poorly constrained, which undermines our understanding of climate change impacts. In recent years, a growing number of studies (often part of GEOTRACES) have used Fe isotopic signatures (δ56Fe) to disentangle different aspects of the marine Fe cycle. Characteristic δ56Fe endmembers of external sources and assumed isotopic fractionation during biological Fe uptake or recycling have been used to estimate relative source contributions and investigate internal transformations, respectively. However, different external sources and fractionation processes often overlap and act simultaneously, complicating the interpretation of oceanic Fe isotope observations. Here we investigate the driving forces behind the marine dissolved Fe isotopic signature (δ56Fediss) distribution by incorporating Fe isotopes into the global ocean biogeochemical model PISCES. We find that distinct external source endmembers acting alongside fractionation during organic complexation and phytoplankton uptake are required to reproduce δ56Fediss observations along GEOTRACES transects. δ56Fediss distributions through the water column result from regional imbalances of remineralization and abiotic removal processes. They modify δ56Fediss directly and transfer surface ocean signals to the interior with opposing effects. Although attributing crustal compositions to sedimentary Fe sources in regions with low organic carbon fluxes improves our isotope model, δ56Fediss signals from hydrothermal or sediment sources cannot be reproduced accurately by simply adjusting δ56Fe endmember values. This highlights that additional processes must govern the exchange and/or speciation of Fe supplied by these sources to the ocean.

Late diagnosis, delayed presentation and late presentation among persons enrolled in a clinical HIV cohort in Ontario, Canada (1999-2013).

OBJECTIVES: Timely HIV diagnosis and presentation to medical care are important for treatment and prevention. Our objective was to measure late diagnosis, delayed presentation and late presentation among individuals in the Ontario HIV Treatment Network Cohort Study (OCS) who were newly diagnosed in Ontario. METHODS: The OCS is a multi-site clinical cohort study of people living with HIV in Ontario, Canada. We measured prevalence of late diagnosis [CD4 count < 350 cells/µL or an AIDS-defining condition (ADC) within 3 months of HIV diagnosis], delayed presentation (≥ 3 months from HIV diagnosis to presentation to care), and late presentation (CD4 count < 350 cells/µL or ADC within 3 months of presentation). We identified characteristics associated with these outcomes and explored their overlap. RESULTS: A total of 1819 OCS participants were newly diagnosed in Ontario from 1999 to 2013. Late diagnosis (53.0%) and presentation (54.0%) were common, and a quarter (23.1%) of participants were delayed presenters. In multivariable models, the participants of delayed presentation decreased over calendar time, but that of late diagnosis/presentation did not. Late diagnosis contributed to the majority (> 87%) of late presentation, and the prevalence of delayed presentation was similar among those diagnosed late versus early (13.4 versus 13.4%, respectively; P = 0.99). Characteristics associated with higher odds of late diagnosis/presentation in multivariable analyses included older age at diagnosis/presentation; African, Caribbean and Black race/ethnicity; Indigenous race/ethnicity; female sex; and being a male who did not report sex with men. There were lower odds of late diagnosis/presentation among participants who had ever injected drugs. In contrast, delayed presentation risk factors included younger age at diagnosis and having ever injected drugs. CONCLUSIONS: Late presentation is common in Ontario, as it is in other high-income countries. Our findings suggest that efforts to reduce late presentation should focus on facilitating earlier diagnosis for the populations identified in this analysis.

Where and when adolescents are physically active: Neighborhood environment and psychosocial correlates and their interactions.

Female adolescents are less active than male peers in certain contexts including the neighborhood. Adolescents' physical activity can be explained by interactions between environmental and psychosocial factors, but few studies have tested such interactions in relation to context-specific behaviors. This study tested interactions between neighborhood environmental and psychosocial factors in relation to adolescents' context-specific physical activity. Data were collected in 2009-11 from 910 adolescents and a parent/guardian residing in the Baltimore/Seattle regions. Measures included adolescent-reported neighborhood leisure-time physical activity (LTPA) and non-neighborhood LTPA, accelerometer-based non-school moderate-to vigorous-physical activity (MVPA), psychosocial factors, and objective and parent-perceived neighborhood environmental factors. Gender-stratified mixed effects linear models tested associations of 6 environmental and 4 psychosocial factors and their interactions in relation to each physical activity outcome. The psychosocial factors had consistent associations with the physical activity outcomes but the environmental correlates were context-specific. Decisional balance (weighing of pros and cons of physical activity) moderated the association between recreation facility density and neighborhood LTPA among females, with a negative association only among those with high decisional balance (pros outweighed cons). Decisional balance also moderated associations of neighborhood walkability with non-school MVPA among females and non-neighborhood LTPA among males, with positive associations only among those with high decisional balance. Results support context-specific ecological models of physical activity. Targeting environmental factors that may promote opportunities for physical activity in specific contexts as well as adolescent decision-making may help promote their physical activity in those contexts, potentially leading to increased overall physical activity.

Collateral Sensitivity to ß-Lactam Drugs in Drug-Resistant Tuberculosis Is Driven by the Transcriptional Wiring of BlaI Operon Genes.

The evolution of resistance to one antimicrobial can result in enhanced sensitivity to another, known as "collateral sensitivity." This underexplored phenomenon opens new therapeutic possibilities for patients infected with pathogens unresponsive to classical treatments. Intrinsic resistance to ß-lactams in Mycobacterium tuberculosis (the causative agent of tuberculosis) has traditionally curtailed the use of these low-cost and easy-to-administer drugs for tuberculosis treatment. Recently, ß-lactam sensitivity has been reported in strains resistant to classical tuberculosis therapy, resurging the interest in ß-lactams for tuberculosis. However, a lack of understanding of the molecular underpinnings of this sensitivity has delayed exploration in the clinic. We performed gene expression and network analyses and in silico knockout simulations of genes associated with ß-lactam sensitivity and genes associated with resistance to classical tuberculosis drugs to investigate regulatory interactions and identify key gene mediators. We found activation of the key inhibitor of ß-lactam resistance, blaI, following classical drug treatment as well as transcriptional links between genes associated with ß-lactam sensitivity and those associated with resistance to classical treatment, suggesting that regulatory links might explain collateral sensitivity to ß-lactams. Our results support M. tuberculosis ß-lactam sensitivity as a collateral consequence of the evolution of resistance to classical tuberculosis drugs, mediated through changes to transcriptional regulation. These findings support continued exploration of ß-lactams for the treatment of patients infected with tuberculosis strains resistant to classical therapies. IMPORTANCE Tuberculosis remains a significant cause of global mortality, with strains resistant to classical drug treatment considered a major health concern by the World Health Organization. Challenging treatment regimens and difficulty accessing drugs in low-income communities have led to a high prevalence of strains resistant to multiple drugs, making the development of alternative therapies a priority. Although Mycobacterium tuberculosis is naturally resistant to ß-lactam drugs, previous studies have shown sensitivity in strains resistant to classical drug treatment, but we currently lack understanding of the molecular underpinnings behind this phenomenon. We found that genes involved in ß-lactam susceptibility are activated after classical drug treatment resulting from tight regulatory links with genes involved in drug resistance. Our study supports the hypothesis that ß-lactam susceptibility observed in drug-resistant strains results from the underlying regulatory network of M. tuberculosis, supporting further exploration of the use of ß-lactams for tuberculosis treatment.

The development of a walkability index: application to the Neighborhood Quality of Life Study.

Emerging evidence supports a link between neighbourhood built environment and physical activity. Systematic methodologies for characterising neighbourhood built environment are needed that take advantage of available population information such as census-level demographics. Based on transportation and urban planning literatures, an integrated index for operationalising walkability using parcel-level information is proposed. Validity of the walkability index is examined through travel surveys among areas examined in the Neighborhood Quality of Life Study (NQLS), a study investigating built environment correlates of adults' physical activity.

Nuclear magnetic resonance measurement of oil "unsaturation" in single viable corn kernels.

High-resolution nuclear magnetic resonance spectroscopy has been used to demonstrate the feasibility of determining iodine value and average molecular weight of oil in individual corn kernels. The procedure is rapid and nondestructive. Depending on heritability of individual fatty acids, this technique may greatly increase selection efficiency in breeding programs to alter the fatty acid composition of corn oil.

Global carbon sinks and their variability inferred from atmospheric O2 and delta13C.

Recent time-series measurements of atmospheric O2 show that the land biosphere and world oceans annually sequestered 1.4 +/- 0.8 and 2.0 +/- 0.6 gigatons of carbon, respectively, between mid-1991 and mid-1997. The rapid storage of carbon by the land biosphere from 1991 to 1997 contrasts with the 1980s, when the land biosphere was approximately neutral. Comparison with measurements of delta13CO2 implies an isotopic flux of 89 +/- 21 gigatons of carbon per mil per year, in agreement with model- and inventory-based estimates of this flux. Both the delta13C and the O2 data show significant interannual variability in carbon storage over the period of record. The general agreement of the independent estimates from O2 and delta13C is a robust signal of variable carbon uptake by both the land biosphere and the oceans.

The Entner-Doudoroff pathway: history, physiology and molecular biology.

The Entner-Doudoroff pathway is now known to be very widely distributed in nature. Biochemical and physiological studies show that the Entner-Doudoroff pathway can operate in a linear and catabolic mode, in a 'cyclic' mode, in a modified mode involving non-phosphorylated intermediates, or in alternative modes involving C1 metabolism and anabolism. Molecular and genetic analyses of the Entner-Doudoroff pathway in Zymomonas mobilis, Escherichia coli and Pseudomonas aeruginosa have led to an improved understanding of some fundamental aspects of metabolic controls. It can be argued that the Entner-Doudoroff pathway is more primitive than Embden-Meyerhof-Parnas glycolysis.

A genome-wide linkage scan for bone mineral density in an extended sample: evidence for linkage on 11q23 and Xq27.

BACKGROUND: Osteoporosis is a major public health problem, mainly quantified by low bone mineral density (BMD). The majority of BMD variation is determined by genetic effects. A pilot whole genome linkage scan (WGS) was previously reported in 53 white pedigrees with 630 subjects. Several genomic regions were suggested to be linked to BMD variation. OBJECTIVE: To substantiate these previous findings and detect new genomic regions. METHODS: A WGS was conducted on an extended sample where the size was almost tripled (1816 subjects from 79 pedigrees). All the subjects were genotyped with 451 microsatellite markers spaced approximately 8.1 cM apart across the human genome. Two point and multipoint linkage analyses were carried out using the variance component method. RESULTS: The strongest linkage signal was obtained on Xq27 with two point LOD scores of 4.30 for wrist BMD, and 2.57 for hip BMD, respectively. Another important region was 11q23, which achieved a maximum LOD score of 3.13 for spine BMD in multipoint analyses, confirming the results on this region in two earlier independent studies. Suggestive linkage evidence was also found on 7p14 and 20p12. CONCLUSIONS: Together with the findings from other studies, the current study has further delineated the genetic basis of bone mass and highlights the importance of increasing sample size to confirm linkage findings and to identify new regions of linkage.

The internist's role in addressing violence. A review of current recommendations and a model for intervention.

Approximately 25,000 people die in the United States each year as the result of intentional homicide, and many millions more suffer the physical and emotional consequences of nonfatal interpersonal violence. Violence affects everybody's quality of life. The cost to the health care system is in the billions of dollars annually. Over the past 2 decades epidemiologic studies have defined risk factors for violence, and a number of physicians and medical groups have made recommendations for preventive action. As the largest physician group in the United States, internists have a clear role to play in carrying out the medical responsibility to help prevent violence. Internists should be aware of the signs and symptoms of violence in patients and be prepared to assist victims. To facilitate action against violence, a model for intervention is proposed that involves screening, counseling, and treatment for patients at greatest risk.

DNA screening for breast/ovarian cancer susceptibility based on linked markers. A family study.

BACKGROUND: Linkage to chromosome 17q has been identified in hereditary breast cancer and hereditary breast/ovarian cancer syndrome. A hereditary breast/ovarian cancer syndrome kindred was identified that yielded a highly significant lod score (4.20) when 17q markers were studied, enabling us to identify those who probably carried the cancer-associated gene among the high-risk members of the family. METHODS: High-risk members of the hereditary breast/ovarian cancer syndrome kindred were offered counselling on the basis of 17q markers. Family members responding positively received one-to-one genetic counseling in a structured setting. Subjects were educated before disclosure, and the immediate impact of this information was assessed after disclosure. RESULTS: We provided genetic counseling on the basis of linkage findings to 32 relatives (four men and 28 women). Women who were told they were linkage positive expressed an increased motivation for surveillance and prophylactic surgery. Most women who were told they were linkage negative indicated that they would not proceed with prophylactic surgery but would continue careful surveillance. To date, there has been no evidence of serious emotional disturbances resulting from this disclosure. We believe that this experience can be used by cancer geneticists and physicians in developing protocols for genetic counseling in cancer-associated hereditary disorders. CONCLUSIONS: Physicians must understand current developments in cancer genetics and linkage so that they can be applied to genetic counseling and treatment of high-risk patients.

Constraints on soluble aerosol iron flux to the Southern Ocean at the Last Glacial Maximum.

Relief of iron (Fe) limitation in the Southern Ocean during ice ages, with potentially increased carbon storage in the ocean, has been invoked as one driver of glacial-interglacial atmospheric CO2 cycles. Ice and marine sediment records demonstrate that atmospheric dust supply to the oceans increased by up to an order of magnitude during glacial intervals. However, poor constraints on soluble atmospheric Fe fluxes to the oceans limit assessment of the role of Fe in glacial-interglacial change. Here, using novel techniques, we present estimates of water- and seawater-soluble Fe solubility in Last Glacial Maximum (LGM) atmospheric dust from the European Project for Ice Coring in Antarctica (EPICA) Dome C and Berkner Island ice cores. Fe solubility was very variable (1-42%) during the interval, and frequently higher than typically assumed by models. Soluble aerosol Fe fluxes to Dome C at the LGM (0.01-0.84 mg m(-2) per year) suggest that soluble Fe deposition to the Southern Ocean would have been ≥10 × modern deposition, rivalling upwelling supply.

Is population bone mineral density variation linked to the marker D11S987 on chromosome 11q12-13?

Our purpose is to test linkage of human chromosome 11q12-13 to BMD variation. Chromosome 11q12-13 has been linked to three BMD-related phenotypes that are inherited as Mendelian traits in human pedigrees: an autosomal dominant high bone mass trait, autosomal recessive osteoporosis pseudoglioma, and autosomal recessive osteopetrosis. A sibling pair study with 374 sibships showed significant linkage of D11S987 to normal BMD variation, with a maximum logarithm of odds score of 3.5. However, a subsequent linkage study with a total of 595 sibling pairs demonstrated reduced significance for linkage of D11S987 to bone mineral density variation, with a logarithm of odds score less than 2.2. We genotyped five markers in a genomic region of approximately 27 cM centering on D11S987 and measured bone mineral density and other traits (weight, etc.) for 635 individuals from 53 human pedigrees. Each of these pedigrees was ascertained through a proband with bone mineral density Z-scores less than -1.28 at the hip or spine. Adjusting for age, sex, and weight as covariates, we performed two-point and multipoint linkage analyses using the variance component linkage analysis method implemented in Sequential Oligogenic Linkage Analysis Routines. We found little evidence of linkage of these five markers to bone mineral density at the spine, hip, wrist and total body bone mineral content. The maximum logarithm of odds score at these five markers was 0.25, and the maximum logarithm of odds score at D11S987 was 0.15. Therefore, although we cannot exclude the linkage of D11S987 region to bone mineral density variation, there is no evidence for linkage of the marker D11S987 on human chromosome 11q12-13 to bone mineral density variation in our study population.

Advantage of monoclonal vs. polyclonal antisera in a beta 2-microglobulin radioimmunoassay.

Unassociated human beta 2-microglobulin (beta 2m) and histocompatibility peptide associated beta 2-microglobulin produce significantly different inhibition curves in a competitive binding assay with rabbit anti-beta 2-microglobulin. This difference disallows the use of the rabbit antisera for measuring MHC-beta 2-microglobulin complex concentration using free beta 2m as a standard. Presumably the close amino acid sequence homology between human and rabbit beta 2-microglobulin results in rabbit antisera against a small number of epitopes, some of which are covered or conformationally altered in the MHC-beta 2-microglobulin complex. A monoclonal anti-beta 2-microglobulin antibody, LG1 reacted equally well with both forms of beta 2-microglobulin and is used to measure the concentration of beta 2-microglobulin in the histocompatibility peptide complex.

Growth of human tumor xenografts in SCID mice quantified using an immunoassay for tumor marker protein in serum.

The accurate measurement of the response of a tumor to a given treatment is critical to evaluating novel therapeutic modalities. An experimental design is reported here that can be generally applied to monitoring human tumor xenografts growing in immunodeficient mice. A human non-small cell lung tumor cell line was transfected with a mammalian expression vector containing the gene encoding human prostate specific antigen (PSA) and has been shown to grow progressively following the subcutaneous, intraperitoneal and intravenous inoculation of the tumor into severe combined immunodeficient (SCID) mice. The transfected human tumor cells produce PSA that accumulates in the sera of all tumor inoculated SCID mice. An enzyme-linked immunoassay using a rabbit polyclonal and a mouse monoclonal antibody specific for PSA was designed and tested for the detection and quantification of serum PSA in tumor-bearing mice. Over a 5-week period, the serum levels of PSA of mice inoculated subcutaneously with the tumor increased progressively, and the estimated tumor volumes correlated with the amount of PSA detected in the serum. Serum PSA levels correlated even better with total tumor mass following the intraperitoneal inoculation of tumor cells into SCID mice. Serum PSA levels fell rapidly following the surgical debulking of tumor xenograft, reaching background levels of PSA in the serum 1 week after tumor removal. Serum PSA levels were also observed in SCID mice inoculated intravenously with a PSA transfected human lung tumor cell line adapted to grow orthotopically in the lung. The transfection of human tumors with a tumor marker and the use of an immunoassay to detect this marker establish an experimental design that provides a reliable, non-invasive, accurate and simple approach to monitor and quantify the growth of human tumor xenografts in SCID mice.

Prodrugs of nitroxyl and nitrosobenzene as cascade latentiated inhibitors of aldehyde dehydrogenase.

The prototypic aromatic C-nitroso compound, nitrosobenzene (NB), was shown previously to mimic the effect of nitroxyl (HN=O), the putative active metabolite of cyanamide, in inhibiting aldehyde dehydrogenase (AlDH). To minimize the toxicity of NB in vivo, pro-prodrug forms of NB, which were designed to be bioactivated either by an esterase intrinsic to AlDH or the mixed function oxidase enzymes of liver microsomes, were prepared. Accordingly, the prodrug N-benzenesulfonyl-N-phenylhydroxylamine (3) was further latentiated by conversion to its O-acetyl (1a), O-methoxycarbonyl (1b), O-ethoxycarbonyl (1c), and O-methyl (2) derivatives. Similarly, pro-prodrug forms of nitroxyl were prepared by derivatization of the hydroxylamino moiety of methanesulfohydroxamic acid with N, O-bis-acetyl (7a), N,O-bis-methoxycarbonyl (7b), N, O-bis-ethoxycarbonyl (7c), and N-methoxycarbonyl-O-methyl (7d) groups. It was expected that the bioactivation of these prodrugs would initiate a cascade of nonenzymatic reactions leading to the ultimate liberation of NB or nitroxyl, thereby inhibiting AlDH. Indeed, the ester pro-prodrugs of both series were highly active in inhibiting yeast AlDH in vitro with IC50 values ranging from 21 to 64 microM. However, only 7d significantly raised ethanol-derived blood acetaldehyde levels when administered to rats, a reflection of the inhibition of hepatic mitochondrial AlDH-2.

Diethylcarbamoylating/nitroxylating agents as dual action inhibitors of aldehyde dehydrogenase: a disulfiram-cyanamide merger.

Benzenesulfohydroxamic acid (Piloty's acid) was functionalized on the hydroxyl group with the N,N-diethylcarbamoyl group, and the hydroxylamine nitrogen was substituted with acetyl (1a), pivaloyl (1b), benzoyl (1c), and ethoxycarbonyl (1d) groups. Only compound 1d inhibited yeast aldehyde dehydrogenase (AlDH) in vitro (IC(50) 169 microM). When administered to rats, 1d significantly raised blood acetaldehyde levels following ethanol challenge, thus serving as a diethylcarbamoylating/nitroxylating, dual action inhibitor of AlDH in vivo. A more potent dual action agent was N-(N, N-diethylcarbamoyl)-O-methylbenzenesulfohydroxamic acid (5c), which was postulated to release diethylcarbamoylnitroxyl (9), a highly potent diethylcarbamoylating/nitroxylating agent, following metabolic O-demethylation in vivo. The dual action inhibition of AlDH exhibited by 1d, and especially 9, constitutes a merger of the mechanism of action of the alcohol deterrent agents, disulfiram and cyanamide.

DNA array analysis in a Microsoft Windows environment.

Microsoft Windows-based computers have evolved to the point that they provide sufficient computational and visualization power for robust analysis of DNA array data. In fact, smaller laboratories might prefer to carry out some or all of their analyses and visualization in a Windows environment, rather than alternative platforms such as UNIX. We have developed a series of manually executed macros written in Visual Basic for Microsoft Excel spreadsheets, that allows for rapid and comprehensive gene expression data analysis. The first macro assigns gene names to spots on the DNA array and normalizes individual hybridizations by expressing the signal intensity for each gene as a percentage of the sum of all gene intensities. The second macro streamlines statistical consideration of the confidence in individual gene measurements for sets of experimental replicates by calculating probability values with the Student's t test. The third macro introduces a threshold value, calculates expression ratios between experimental conditions, and calculates the standard deviation of the mean of the log ratio values. Selected columns of data are copied by a fourth macro to create a processed data set suitable for entry into a Microsoft Access database. An Access database structure is described that allows simple queries across multiple experiments and export of data into third-party data visualization software packages. These analysis tools can be used in their present form by others working with commercial E. coli membrane arrays, or they may be adapted for use with other systems. The Excel spreadsheets with embedded Visual Basic macros and detailed instructions for their use are available at http://www.ou.edu/microarray.