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"Nielsen, D. A."
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Broad scale proteomic analysis of heat-destabilised symbiosis in the hard coral Acropora millepora
Coral reefs across the globe are threatened by warming oceans. The last few years have seen the worst mass coral bleaching events recorded, with more than one quarter of all reefs irreversibly impacted. Considering the widespread devastation, we need to increase our efforts to understanding the physiological and metabolic shifts underlying the breakdown of this important symbiotic ecosystem. Here, we investigated the proteome (PRIDE accession # PXD011668) of both host and symbionts of the reef-building coral
Acropora millepora
exposed to ambient (~ 28 °C) and elevated temperature (~ 32 °C for 2 days, following a five-day incremental increase) and explored associated biomolecular changes in the symbiont, with the aim of gaining new insights into the mechanisms underpinning the collapse of the coral symbiosis. We identified 1,230 unique proteins (774 host and 456 symbiont) in the control and thermally stressed corals, of which 107 significantly increased and 125 decreased in abundance under elevated temperature relative to the control. Proteins involved in oxidative stress and proteolysis constituted 29% of the host proteins that increased in abundance, with evidence of impairment to endoplasmic reticulum and cytoskeletal regulation proteins. In the symbiont, we detected a decrease in proteins responsible for photosynthesis and energy production (33% of proteins decreased in abundance), yet minimal signs of oxidative stress or proteolysis. Lipid stores increased > twofold despite reduction in photosynthesis, suggesting reduced translocation of carbon to the host. There were significant changes in proteins related to symbiotic state, including proteins linked to nitrogen metabolism in the host and the V-ATPase (-0.6 fold change) known to control symbiosome acidity. These results highlight key differences in host and symbiont proteomic adjustments under elevated temperature and identify two key proteins directly involved in bilateral nutrient exchange as potential indicators of symbiosis breakdown.
Journal Article
Genotype patterns that contribute to increased risk for or protection from developing heroin addiction
A genome-wide association study was conducted using microarray technology to identify genes that may be associated with the vulnerability to develop heroin addiction, using DNA from 104 individual former severe heroin addicts (meeting Federal criteria for methadone maintenance) and 101 individual control subjects, all Caucasian. Using separate analyses for autosomal and X chromosomal variants, we found that the strongest associations of allele frequency with heroin addiction were with the autosomal variants rs965972, located in the Unigene cluster Hs.147755 (experiment-wise q=0.053), and rs1986513 (q=0.187). The three variants exhibiting the strongest association with heroin addiction by genotype frequency were rs1714984, located in an intron of the gene for the transcription factor myocardin (
P
=0.000022), rs965972 (
P
=0.000080) and rs1867898 (
P
=0.000284). One genotype pattern (AG-TT-GG) was found to be significantly associated with developing heroin addiction (odds ratio (OR)=6.25) and explained 27% of the population attributable risk for heroin addiction in this cohort. Another genotype pattern (GG-CT-GG) of these variants was found to be significantly associated with protection from developing heroin addiction (OR=0.13), and lacking this genotype pattern explained 83% of the population attributable risk for developing heroin addiction. Evidence was found for involvement of five genes in heroin addiction, the genes coding for the μ opioid receptor, the metabotropic receptors mGluR6 and mGluR8, nuclear receptor NR4A2 and cryptochrome 1 (photolyase-like). This approach has identified several new genes potentially associated with heroin addiction and has confirmed the role of
OPRM1
in this disease.
Journal Article
Uptake of dimethylsulphoniopropionate (DMSP) by the diatom Thalassiosira weissflogii
One of the most abundant organic sulphur molecules in the ocean, dimethylsulphoniopropionate (DMSP) has been implicated in numerous biochemical functions and ecological interactions, from osmotic and oxidative stress regulation within the cell, to the chemical attraction of bacteria, mammals and birds in the environment. Notwithstanding these varied and important discoveries, the primary role of DMSP in the cell remains elusive. In this study, we take a new approach to investigating the role of DMSP in cell physiology. Rather than utilising a known DMSP-producer, we instead exploit the propensity for the non-DMSP producing diatom Thalassiosira weissflogii to take up DMSP from its environment. We characterise the uptake and retention of the molecule under growth conditions and salinity stress with the aim to elucidate its utility as a model system for investigating the cellular function of DMSP. Thalassiosira weissflogii showed concentration-dependent uptake of DMSP and complete retention within the cell for at least 6 h. Saturation of intracellular DMSP occurred at < 87 mM, equivalent to some of the most prolific DMSP-producing species. Salinity shifts resulted in a reduction in DMSP uptake rate, but only at extremely low (17) or very high (45) salinities. These data demonstrate the potential for using T. weissflogii in physiological studies, providing a true (DMSP-free) control, as well as a DMSP-enriched version of the same strain. In this way, orthogonal experiments may be conducted with the aim to uncover the physiological purpose of DMSP in phytoplankton and potentially add key pieces to the enigmatic DMSP puzzle.
Journal Article
Characterisation of coral explants: a model organism for cnidarian–dinoflagellate studies
Coral cell cultures made from reef-building scleractinian corals have the potential to aid in the pursuit of understanding of the cnidarian–dinoflagellate symbiosis. Various methods have previously been described for the production of cell cultures in vitro with a range of success and longevity. In this study, viable tissue spheroids containing host tissue and symbionts (coral explants) were grown from the tissues of
Fungia granulosa
. The cultured explants remained viable for over 2 months and showed morphological similarities in tissue structure and internal microenvironment to reef-building scleractinian corals. The photophysiology of the explants (1 week old) closely matched that of the parent coral
F. granulosa
. This study provides the first empirical basis for supporting the use of coral explants as laboratory models for studying coral symbioses. In particular, it highlights how these small, self-sustaining, skeleton-free models can be useful for a number of molecular, genetic and physiological analyses necessary for investigating host–symbiont interactions at the microscale.
Journal Article
Identification of four variants in the tryptophan hydroxylase promoter and association to behavior
One of the most replicated findings in biological psychiatry is the observation of lower 5-hydroxyindoleacetic acid concentrations, the major metabolite of serotonin, in the brain and cerebrospinal fluid of subjects with impulsive aggression. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin, however functional variants have not been reported from the coding sequence of this gene. Therefore, we screened the human TPH promoter (TPH-P) for genetic variants which could modulate TPH gene transcription. The TPH-P (2093 nucleotides) was screened for sequence variation by SSCP analysis of 260 individuals from Finnish, Italian, American Caucasian, and American Indian populations. Four common polymorphisms were identified: −7180T>G, −7065C>T, −6526A>G, and −5806G>T (designated as nucleotides upstream of the translation start site). In the Finns, the four polymorphisms had a minor allele frequency of 0.40 and in this population linkage disequilibrium between the four loci was complete. In the other populations the minor allele frequencies ranged from 0.40 to 0.45. TPH −6526A>G genotype was determined in 167 unrelated Finnish offenders and 153 controls previously studied for the TPH IVS7+779C>A polymorphism. A significant association was observed between −6526A>G and suicidality in the offenders. TPH −6526A>G and the previously reported intron seven polymorphism, TPH IVS7+779C>A, exhibited a normalised linkage disequilibrium of 0.89 in Finns. Normalized linkage disequilibrium was reduced in other populations, being 0.49 and 0.21 in Italians and American Indians, respectively. In conclusion, four TPH-P variants were identified which can be used for haplotype-based analysis to localize functional TPH alleles influencing behavior.
Journal Article
Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity
Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity’) that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT
2C
receptor (5-HT
2C
R) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the
HTR2C
gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT
2C
R protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT
2C
R agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT
2C
R system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.
Journal Article
Catalytic Reduction of Nitric Oxide by Hydrogen Sulfide Over γ-alumina
The ability of H2S to reduce NO in a fixed bed reactor using a γ-alumina catalyst was studied with the objective of generating new methods for conversion of NO to N2. Compared to the homogenous reaction of NO with H2S, the catalyzed reaction showed improved conversions of NO to N2. Using a gas space velocity of 1000 h−1 and a feed of 1% NO and 1% H2S in argon, it was found that the conversion of NO to N2 was complete at 800 °C. This result compared to a 38% conversion of NO to N2 for the homogeneous gas phase reaction at 800 °C. At temperatures below 800 °C, a short fall in the nitrogen balance was discovered when the γ-alumina was employed as a catalyst. This discrepancy was explained by conversion of NO to NH3 and subsequent reaction of the NH3 with any SO2 in the system to form ammonium sulfur oxy-anion salts. This suggestion is supported by the finding that when larger amounts of H2S were used relative to NO, more NH3 was formed together in tandem with lower N2 mass balances. Several reaction pathways have been proposed for the catalytic reduction of NO by H2S.
Journal Article
Prediction of Bacteremia Using TREAT, a Computerized Decision-Support System
Background. Prediction of bloodstream infection at the time of sepsis onset allows one to make appropriate and economical management decisions. Methods. The TREAT computerized decision-support system uses a causal probabilistic network, which is locally calibrated, to predict cases of bacteremia. We assessed the system's performance in 2 independent cohorts that included patients with suspected sepsis. Both studies were conducted in Israel, Italy, and Germany. Data were collected prospectively and were entered into the TREAT system at the time that blood samples were obtained for culture. Discriminative power was assessed using a receiver-operating characteristics curve. Results. In the first cohort, 790 patients were included. The area under the receiver-operating characteristics curve for prediction of bacteremia using the TREAT system was 0.68 (95% confidence interval [CI], 0.63–0.73). We used TREAT's prediction values to draw thresholds defining a low-, intermediate-, and high-risk groups for bacteremia, in which 3 (2.4%) of 123, 62 (12.8%) of 483, and 55 (29.9%) of 184 patients were bacteremic, respectively. In the second cohort, 1724 patients were included. The area under the receiver-operating characteristics curve was 0.70 (95% CI, 0.67–0.73). The prevalence of bacteremia observed in the low-, intermediate-, and high-risk groups defined by the first cohort were 1.3% (4 of 300 patients), 13.2% (150 of 1139 patients), and 28.1% (80 of 285 patients), respectively. The low-risk groups in the 2 cohorts comprised 15%–17% of all patients. Performance was stable in the 3 sites. Conclusions. Using variables available at the time that blood cultures were performed, the TREAT system successfully stratified patients on the basis of the risk for bacteremia. The system's predictions were stable in 3 locations. The TREAT system can define a low-risk group of inpatients with suspected sepsis for whom blood cultures may not be needed.
Journal Article