Bisphenol A sulfonation is impaired in metabolic and liver disease

Background: Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. Objectives: To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. Methods: The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. Results: In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. Conclusion: Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers

Theology, News and Notes - Vol. 53, No. 02

Theology News & Notes was a theological journal published by Fuller Theological Seminary from 1954 through 2014.https://digitalcommons.fuller.edu/tnn/1156/thumbnail.jp

Monoamine Neurotransmitters as Substrates for Novel Tick Sulfotransferases, Homology Modeling, Molecular Docking, and Enzyme Kinetics

Blacklegged ticks (Ixodes scapularis) transmit the causative agent of Lyme disease in the Northeastern United States. Current research focuses on elucidating biochemical pathways that may be disrupted to prevent pathogen transmission, thereby preventing disease. Genome screening reported transcripts coding for two putative sulfotransferases in whole tick extracts of the nymphal and larval stages. Sulfotransferases are known to sulfonate phenolic and alcoholic receptor agonists such as 17β-estradiol, thereby inactivating the receptor ligands. We used bioinformatic approaches to predict substrates for Ixosc Sult 1 and Ixosc Sult 2 and tested the predictions with biochemical assays. Homology models of 3D protein structure were prepared, and visualization of the electrostatic surface of the ligand binding cavities showed regions of negative electrostatic charge. Molecular docking identified potential substrates including dopamine, R-octopamine and S-octopamine, which docked into Ixosc Sult 1 with favorable binding affinity and correct conformation for sulfonation. Dopamine, but not R- or S-octopamine, also docked into Ixosc Sult 2 in catalytic binding mode. The predictions were confirmed using cytosolic fractions of whole tick extracts. Dopamine was a good substrate (Km = 0.1−0.4 μM) for the native Ixodes scapularis sulfotransferases from larval and nymphal stages regardless of their fed/unfed status. Octopamine sulfonation was detected only after feeding when gene expression data suggests that Ixosc Sult 1 is present. Because dopamine is known to stimulate salivation in ticks through receptor stimulation, these results imply that the function(s) of Ixosc Sult 1 or 2 may include inactivation of the salivation signal via sulfonation of dopamine and/or octopamine

Molecular characterization of novel sulfotransferases from the tick, Ixodes scapularis

<p>Abstract</p> <p>Background</p> <p><it>Ixodes scapularis</it>, commonly known as the blacklegged or deer tick, is the main vector of Lyme disease in the United States. Recent progress in transcriptome research has uncovered hundreds of different proteins expressed in the salivary glands of hard ticks, the majority of which have no known function, and include many novel protein families. We recently identified transcripts coding for two putative cytosolic sulfotransferases in these ticks which recognized phenolic monoamines as their substrates. In this current study, we characterize the genetic expression of these two cytosolic sulfotransferases throughout the tick life cycle as well as the enzymatic properties of the corresponding recombinant proteins. Interestingly, the resultant recombinant proteins showed sulfotransferase activity against both neurotransmitters dopamine and octopamine.</p> <p>Results</p> <p>The two sulfotransferase genes were coded as <it>Ixosc </it>SULT 1 & 2 and corresponding proteins were referred as <it>Ixosc </it>Sult 1 and 2. Using gene-specific primers, the sulfotransferase transcripts were detected throughout the blacklegged tick life cycle, including eggs, larvae, nymphs, adult salivary glands and adult midgut. Notably, the mRNA and protein levels were altered upon feeding during both the larval and nymphal life stages. Quantitative PCR results confirm that <it>Ixosc </it>SULT1 was statistically increased upon blood feeding while <it>Ixosc </it>SULT 2 was decreased. This altered expression led us to further characterize the function of these proteins in the Ixodid tick. The sulfotransferase genes were cloned and expressed in a bacterial expression system, and purified recombinant proteins <it>Ixosc </it>Sult 1(R) and 2(R) showed sulfotransferase activity against neurotransmitters dopamine and octopamine as well as the common sulfotransferase substrate <it>p-</it>nitrophenol. Thus, dopamine- or octopamine-sulfonation may be involved in altering the biological signal for salivary secretion in <it>I. scapularis.</it></p> <p>Conclusions</p> <p>Collectively, these results suggest that a function of <it>Ixosc </it>Sult 1 and Sult 2 in <it>Ixodid </it>tick salivary glands may include inactivation of the salivation signal via sulfonation of dopamine or octopamine.</p

Informational environments: Organizational contexts of online information use

Before the Web, the story of online information services was largely one of over-estimates and unmet expectations. This study examines sustained use and non-use of online services within organizations in a way that overcomes limitations of the traditional approaches that repeatedly led to exuberant usage projections. By adopting an open-systems view, we see that firms in highly technical and highly institutional environments have many more incentives to gather data and go online than do firms in low-tech, unregulated industries. But firms make important choices about partnering and outsourcing that can shift informational activities across organizational boundaries. Our analysis focuses on the informational environments of firms in three industries: law, real estate and biotech/pharmaceuticals. This environmental model provides richer conceptualizations about the use of information and communication technologies, including Internet technologies, and better projections about future use. In support of our analysis, we briefly discuss insights from an ongoing intranets study informed by an informational environments perspective.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48708/1/10182_ftp.pd

Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome

Between 1988 and 1999, 127 patients with poor-risk acute lymphoblastic leukemia (ALL) received a matched unrelated donor transplant using marrow procured by National Marrow Donor Program (NMDP) collection centers and sent out to 46 transplant centers worldwide. Poor risk was defined by the presence of the translocations t(9;22) (n = 97), or t(4;11) (n = 25), or t(1;19) (n = 5). Sixty-four patients underwent transplantation in first remission (CR1), 16 in CR2 or CR3, and 47 patients had relapsed ALL or primary induction failure (PIF). Overall survival at 2 years from transplant was 40% for patients in CR1, 17% in CR2/3, and 5% in PIF or relapse. Treatment-related mortality (TRM) and relapse mortality, estimated as competing risk factors, were 54% and 6%, respectively, in CR1, 75% and 8% in CR2/3, and 64% and 31% in PIF or relapse. Currently 23 CR1 patients are alive and free of disease with a median follow-up of 24 months (range, 3-97). Multivariable analysis showed that CR1, shorter interval from di

Twenty Years of Unrelated Donor Bone Marrow Transplantation for Pediatric Acute Leukemia Facilitated by the National Marrow Donor Program

AbstractThe National Marrow Donor Program (NMDP) has facilitated unrelated donor hematopoietic cell transplants for more than 20 years. In this time period, there have been many changes in clinical practice, including improvements in HLA typing and supportive care, and changes in the source of stem cells. Availability of banked unrelated donor cord blood (incorporated into the NMDP registry in 2000) as a source of stem cells has become an important option for children with leukemia, offering the advantages of immediate availability for children with high-risk disease, the need for a lesser degree of HLA match, and expanding access for those with infrequent HLA haplotypes. Overall survival (OS) in children with acute leukemia transplanted with unrelated donor bone marrow (BM) is markedly better in more recent years, largely attributable to less treatment-related mortality (TRM). Within this cohort, 2-year survival was markedly better for patients with acute lymphoblastic leukemia (ALL) in first complete response (CR1) (74%) versus second complete response (CR2) (62%) or more advanced disease (33%). Similar findings are observed with patients with AML, suggesting earlier referral to bone marrow transplant (BMT) is optimal for survival. Notably, this improvement over time was not observed in unmodified peripheral blood stem cell (PBSC) recipients, suggesting unmodified PBSC may not be the optimal stem cell source for children

Differential modulation of farnesoid X receptor signaling pathway by the thiazolidinediones

ABSTRACT Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are agonists of peroxisome proliferator-activated receptor (PPAR)-␥ and belong to a class of insulin-sensitizing drugs for type 2 diabetes mellitus. However, memberspecific, PPAR␥-independent activities and toxicity have been reported, especially for troglitazone. Currently, the underlying mechanisms are not fully understood. In this study, we demonstrated that troglitazone but not rosiglitazone or pioglitazone modulated expression of farnesoid X receptor (FXR) target genes bile salt export pump (BSEP) and small heterodimer partner (SHP) in Huh-7 cells. More specifically, troglitazone acted as a partial agonist of FXR to weakly increase BSEP and SHP expression but functioned as a potent antagonist to significantly suppress bile acid-induced expression. Consistent with the finding, troglitazone partially induced but markedly antagonized bile acid-mediated BSEP promoter transactivation. However, such modulating effects were not detected with rosiglitazone or pioglitazone. Using the crystal structure of ligand-bound FXR ligand binding domain (LBD), molecular docking predicted that troglitazone, but not rosiglitazone or pioglitazone, could form a stable complex with FXR LBD. The specific ␣-tocopherol side chain of troglitazone significantly contributed to the formation of such a stable complex through extensive interactions with FXR LBD. The docking model was further validated by functional analyses of a series of dockingguided FXR mutants. In summary, the data demonstrated that troglitazone, but not rosiglitazone or pioglitazone, was an FXR modulator and potently antagonized bile acid-induced expression of FXR target genes. Such differential modulation of FXR signaling pathway by TZDs may represent one of the mechanisms for member-specific, PPAR␥-independent activities and toxicity. Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are a class of insulin-sensitizing drugs to treat type 2 diabetes mellitus. Such therapeutic effect of TZDs is achieved through activating nuclear receptor peroxisome proliferator-activated receptor (PPAR)-␥, which is directly involved in the regulation of genes controlling glucose homeostasis and lipid metabolism. Studies also show that TZDs exhibit other important activities, such as cardiovascular, hypertension, and anticancer effects in a PPAR␥-dependent or -independent manne

The effects of interoperable information technology networks on patient safety: a realist synthesis

Background Interoperable networks connect information technology systems of different organisations, allowing professionals in one organisation to access patient data held in another one. Health policy-makers in many countries believe that they will improve the co-ordination of services and, hence, the quality of services and patient safety. To the best of our knowledge, there have not been any previous systematic reviews of the effects of these networks on patient safety. Objectives The aim of the study was to establish how, why and in what circumstances interoperable information technology networks improved patient safety, failed to do so or increased safety risks. The objectives of the study were to (1) identify programme theories and prioritise theories to review; (2) search systematically for evidence to test the theories; (3) undertake quality appraisal, and use included texts to support, refine or reject programme theories; (4) synthesise the findings; and (5) disseminate the findings to a range of audiences. Design Realist synthesis, including consultation with stakeholders in nominal groups and semistructured interviews. Settings and participants Following a stakeholder prioritisation process, several domains were reviewed: older people living at home requiring co-ordinated care, at-risk children living at home and medicines reconciliation services for any patients living at home. The effects of networks on services in health economies were also investigated. Intervention An interoperable network that linked at least two organisations, including a maximum of one hospital, in a city or region. Outcomes Increase, reduction or no change in patients’ risks, such as a change in the risk of taking an inappropriate medication. Results We did not find any detailed accounts of the ways in which interoperable networks are intended to work and improve patient safety. Theory fragments were identified and used to develop programme and mid-range theories. There is good evidence that there are problems with the co-ordination of services in each of the domains studied. The implicit hypothesis about interoperable networks is that they help to solve co-ordination problems, but evidence across the domains showed that professionals found interoperable networks difficult to use. There is insufficient evidence about the effectiveness of interoperable networks to allow us to establish how and why they affect patient safety. Limitations The lack of evidence about patient-specific measures of effectiveness meant that we were not able to determine ‘what works’, nor any variations in what works, when interoperable networks are deployed and used by health and social care professionals. Conclusions There is a dearth of evidence about the effects of interoperable networks on patient safety. It is not clear if the networks are associated with safer treatment and care, have no effects or increase clinical risks. Future work Possible future research includes primary studies of the effectiveness of interoperable networks, of economies of scope and scale and, more generally, on the value of information infrastructures. Study registration This study is registered as PROSPERO CRD42017073004. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 40. See the NIHR Journals Library website for further project information