Flavin-containing monooxygenase mediated metabolism of psychoactive drugs by human brain microsomes

Flavin-containing monooxygenases (FMO) catalyze the oxidation of certain xenobiotics and drugs which contain a nucleophilic heteroatom. Here we report the first assessment of human brain flavin-containing monooxygenase from tissues obtained at autopsy from seven traffic accident victims. Human brain microsomes catalyzed the S-oxidation or N-oxidation of model substrates methimazole and N,N-dimethylaniline, respectively. The psychoactive drugs chlorpromazine, imipramine and fluoxetine, were also metabolized by human brain FMO. 'Western' immunoblot analyses revealed immunological cross-reactivity of the human brain FMO with rabbit pulmonary FMO. Immunocytochemistry further revealed the localization of the FMO predominantly in the neuronal cell bodies in the magnocellular reticular nuclei, colliculi and substantia nigra. Human brain clearly contains an active FMO system, and it is conceivable that such enzyme(s) are significantly involved in the local metabolism and modulation of pharmacological effects of psychoactive drugs

Exceptional molecular and coreceptor-requirement properties of molecular clones isolated from an Human Immunodeficiency Virus Type-1 subtype C infection

<p>Abstract</p> <p>Background</p> <p>The pathogenic significance of coreceptor switch in the viral infection of HIV-1 is not completely understood. This situation is more complex in subtype C infection where coreceptor switch is either absent or extremely rare. To gain insights into the mechanisms that underlie coreceptor requirement of subtype C, we screened several primary viral isolates and identified a clinical sample that demonstrated a potential to grow on standard T-cell lines with no detectable CCR5 expression. The subject was diagnosed with HIV-1 associated dementia in the absence of opportunistic infections of the brain. To isolate molecular clones from this virus, we devised a novel strategy based on anchor primers that target a sequence in the reverse transcriptase, highly conserved among diverse subtypes of HIV-1.</p> <p>Results</p> <p>Using this strategy, we isolated 8 full-length molecular clones from the donor. Two of the eight molecular clones, 03In94_D17 and 03In94_D24, (D17 and D24) generated replication-competent viruses. Phylogenetic analysis of the full-length viral sequences revealed that both clones were non-recombinant subtype C viruses. They contain intact open reading frames in all the viral proteins. Both the viral clones are endowed with several unique molecular and biological properties. The viral promoter of the clones is characterized by the presence of four NF-kB binding elements, a feature rarely seen in the subtype C HIV-1 LTR. Interestingly, we identified the coexistence of two different forms of Rev, a truncated form common to subtype C and a full-length form less common for this subtype, in both proviral and plasma virus compartments. An exceptional property of the viruses, atypical of subtype C, is their ability to use a wide range of coreceptors including CCR5, CXCR4, and several others tested. Sequence analysis of Env of D17 and D24 clones identified differences within the variable loops providing important clues for the expanded coreceptor use. The V1, V2 and V4 loops in both of the molecular clones are longer due to the insertion of several amino acid residues that generated potential N-linked glycosylation sites.</p> <p>Conclusion</p> <p>The exceptional biological and molecular properties of these clones make them invaluable tools to understand the unique pathogenic characteristics of subtype C.</p

Prevalence of admission plasma glucose in 'diabetes' or 'at risk' ranges in hospital emergencies with no prior diagnosis of diabetes by gender, age and ethnicity

Aims To establish the prevalence of admission plasma glucose in 'diabetes' and 'at risk' ranges in emergency hospital admissions with no prior diagnosis of diabetes; characteristics of people with hyperglycaemia; and factors influencing glucose measurement. Methods Electronic patient records for 113 097 hospital admissions over 1 year from 2014 to 2015 included 43 201 emergencies with glucose available for 31 927 (74%) admissions, comprising 22 045 people. Data are presented for 18 965 people with no prior diagnosis of diabetes and glucose available on first attendance. Results Three quarters (14 214) were White Europeans aged 62 (43-78) years, median (IQ range); 12% (2241) South Asians 46 (32-64) years; 9% (1726) Unknown/Other ethnicities 43 (29-61) years; and 4% (784) Afro-Caribbeans 49 (33-63) years,  24 hours. Conclusions Hyperglycaemia was evident in 21% of adults admitted as an emergency; various aspects related to follow-up and initial testing, age and ethnicity need to be considered by professional bodies addressing undiagnosed diabetes in hospital admissions

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

Cardiac Glycosides Ouabain and Digoxin Interfere with the Regulation of Glutamate Transporter GLAST in Astrocytes Cultured from Neonatal Rat Brain

Glutamate transport (GluT) in brain is mediated chiefly by two transporters GLT and GLAST, both driven by ionic gradients generated by (Na+, K+)-dependent ATPase (Na+/K+-ATPase). GLAST is located in astrocytes and its function is regulated by translocations from cytoplasm to plasma membrane in the presence of GluT substrates. The phenomenon is blocked by a naturally occurring toxin rottlerin. We have recently suggested that rottlerin acts by inhibiting Na+/K+-ATPase. We now report that Na+/K+-ATPase inhibitors digoxin and ouabain also blocked the redistribution of GLAST in cultured astrocytes, however, neither of the compounds caused detectable inhibition of ATPase activity in cell-free astrocyte homogenates (rottlerin inhibited app. 80% of Pi production from ATP in the astrocyte homogenates, IC50 = 25 μM). Therefore, while we may not have established a direct link between GLAST regulation and Na+/K+-ATPase activity we have shown that both ouabain and digoxin can interfere with GluT transport and therefore should be considered potentially neurotoxic

A Literature Review on Cloud Computing Adoption Issues in Enterprises

Part 3: Creating Value through ApplicationsInternational audienceCloud computing has received increasing interest from enterprises since its inception. With its innovative information technology (IT) services delivery model, cloud computing could add technical and strategic business value to enterprises. However, cloud computing poses highly concerning internal (e.g., Top management and experience) and external issues (e.g., regulations and standards). This paper presents a systematic literature review to explore the current key issues related to cloud computing adoption. This is achieved by reviewing 51 articles published about cloud computing adoption. Using the grounded theory approach, articles are classified into eight main categories: internal, external, evaluation, proof of concept, adoption decision, implementation and integration, IT governance, and confirmation. Then, the eight categories are divided into two abstract categories: cloud computing adoption factors and processes, where the former affects the latter. The results of this review indicate that enterprises face serious issues before they decide to adopt cloud computing. Based on the findings, the paper provides a future information systems (IS) research agenda to explore the previously under-investigated areas regarding cloud computing adoption factors and processes. This paper calls for further theoretical, methodological, and empirical contributions to the research area of cloud computing adoption by enterprises

Calculating Stage Duration Statistics in Multistage Diseases

Many human diseases are characterized by multiple stages of progression. While the typical sequence of disease progression can be identified, there may be large individual variations among patients. Identifying mean stage durations and their variations is critical for statistical hypothesis testing needed to determine if treatment is having a significant effect on the progression, or if a new therapy is showing a delay of progression through a multistage disease. In this paper we focus on two methods for extracting stage duration statistics from longitudinal datasets: an extension of the linear regression technique, and a counting algorithm. Both are non-iterative, non-parametric and computationally cheap methods, which makes them invaluable tools for studying the epidemiology of diseases, with a goal of identifying different patterns of progression by using bioinformatics methodologies. Here we show that the regression method performs well for calculating the mean stage durations under a wide variety of assumptions, however, its generalization to variance calculations fails under realistic assumptions about the data collection procedure. On the other hand, the counting method yields reliable estimations for both means and variances of stage durations. Applications to Alzheimer disease progression are discussed

Advances in Social Media Research:Past, Present and Future

Social media comprises communication websites that facilitate relationship forming between users from diverse backgrounds, resulting in a rich social structure. User generated content encourages inquiry and decision-making. Given the relevance of social media to various stakeholders, it has received significant attention from researchers of various fields, including information systems. There exists no comprehensive review that integrates and synthesises the findings of literature on social media. This study discusses the findings of 132 papers (in selected IS journals) on social media and social networking published between 1997 and 2017. Most papers reviewed here examine the behavioural side of social media, investigate the aspect of reviews and recommendations, and study its integration for organizational purposes. Furthermore, many studies have investigated the viability of online communities/social media as a marketing medium, while others have explored various aspects of social media, including the risks associated with its use, the value that it creates, and the negative stigma attached to it within workplaces. The use of social media for information sharing during critical events as well as for seeking and/or rendering help has also been investigated in prior research. Other contexts include political and public administration, and the comparison between traditional and social media. Overall, our study identifies multiple emergent themes in the existing corpus, thereby furthering our understanding of advances in social media research. The integrated view of the extant literature that our study presents can help avoid duplication by future researchers, whilst offering fruitful lines of enquiry to help shape research for this emerging field

Practical approaches to analyzing PTA data: Cosmic strings with six pulsars

We search for a stochastic gravitational wave background (SGWB) generated by a network of cosmic strings using six millisecond pulsars from Data Release 2 (DR2) of the European Pulsar Timing Array (EPTA). We perform a Bayesian analysis considering two models for the network of cosmic string loops, and compare it to a simple power-law model which is expected from the population of supermassive black hole binaries. Our main strong assumption is that the previously reported common red noise process is a SGWB. We find that the one-parameter cosmic string model is slightly favored over a power-law model thanks to its simplicity. If we assume a two-component stochastic signal in the data (supermassive black hole binary population and the signal from cosmic strings), we get a $95\%$ upper limit on the string tension of $\log_{10}(G\mu) < -9.9$ ($-10.5$) for the two cosmic string models we consider. In extended two-parameter string models, we were unable to constrain the number of kinks. We test two approximate and fast Bayesian data analysis methods against the most rigorous analysis and find consistent results. These two fast and efficient methods are applicable to all SGWBs, independent of their source, and will be crucial for analysis of extended data sets.Comment: 13 pages, 5 figure