A Single Residue Switch Converts Abietadiene Synthase into a Pimaradiene Specific Cyclase

Terpene synthases often catalyze complex cyclization reactions that typically represent the committed step in particular biosynthetic pathways, leading to great interest in their enzymatic mechanisms. We have recently demonstrated that substitution of a specific Ile with Thr was sufficient to “short circuit” the complex cyclization reaction normally catalyzed by ent-kaurene synthases to instead produce ent-pimaradiene. Here we report that the complex cyclization/rearrangement reaction catalyzed by abietadiene synthase can be similarly cut short to produce pimaradienes by an analogous Ser for Ala change, albeit with a slight shift in active site location to accommodate the difference in substrate stereochemistry. This result has mechanistic implications for enzymatic catalysis of abietadiene cyclization, and terpene synthases more broadly. Furthermore, these defined single residue switches may be useful in engineering product outcome in diterpene synthases more generally

A Modular Approach for Facile Biosynthesis of Labdane-Related Diterpenes

Labdane-related diterpenoids are a large group of over 5,000 natural products whose biosynthesis typically proceeds through a labdadienyl/copalyl diphosphate (CPP) intermediate to a further cyclized and/or rearranged hydrocarbon diterpene en route to more elaborated compounds. Here we report a modular approach for facile biosynthesis of labdane-related diterpenes wherein base pGGxC vectors capable of introducing bacterial production of any one of the three common stereoisomers of CPP can be co-introduced with diterpene synthases that convert these CPP intermediates to specific diterpene hydrocarbon skeletal structures. The utility of this approach is demonstrated by individually engineering E. coli to produce any one of eight different diterpene skeletal structures, which collectively serve as precursors to literally thousands of distinct natural products

Local interaction Strategies and Capacity for Better Care in Nursing Homes: A Multiple Case Study

To describe relationship patterns and management practices in nursing homes (NHs) that facilitate or pose barriers to better outcomes for residents and staff. Methods: We conducted comparative, multiple-case studies in selected NHs (N = 4). Data were collected over six months from managers and staff (N = 406), using direct observations, interviews, and document reviews. Manifest content analysis was used to identify and explore patterns within and between cases. Results: Participants described interaction strategies that they explained could either degrade or enhance their capacity to achieve better outcomes for residents; people in all job categories used these 'local interaction strategies'. We categorized these two sets of local interaction strategies as the 'common pattern' and the 'positive pattern' and summarize the results in two models of local interaction. Conclusions: The findings suggest the hypothesis that when staff members in NHs use the set of positive local interaction strategies, they promote inter-connections, information exchange, and diversity of cognitive schema in problem solving that, in turn, create the capacity for delivering better resident care. We propose that these positive local interaction strategies are a critical driver of care quality in NHs. Our hypothesis implies that, while staffing levels and skill mix are important factors for care quality, improvement would be difficult to achieve if staff members are not engaged with each other in these ways.National Institutes of Health 2 R01NR003178-04A2Claude A. Pepper Older American's Independence Center AG-11268Paul A. Beeson Award NIA AG024787VA Health Services Research and Development EDU 08-417John A. Hartford Building Academic Geriatric Nursing Claire M. Fagin FellowshipBusiness Administratio

Spreading dynamics on spatially constrained complex brain networks

The study of dynamical systems defined on complex networks provides a natural framework with which to investigate myriad features of neural dynamics and has been widely undertaken. Typically, however, networks employed in theoretical studies bear little relation to the spatial embedding or connectivity of the neural networks that they attempt to replicate. Here, we employ detailed neuroimaging data to define a network whose spatial embedding represents accurately the folded structure of the cortical surface of a rat brain and investigate the propagation of activity over this network under simple spreading and connectivity rules. By comparison with standard network models with the same coarse statistics, we show that the cortical geometry influences profoundly the speed of propagation of activation through the network. Our conclusions are of high relevance to the theoretical modelling of epileptic seizure events and indicate that such studies which omit physiological network structure risk simplifying the dynamics in a potentially significant way

Integrating invasion and disease in the risk assessment of live bird trade.

AimInternational trade in plants and animals generates significant economic benefits. It also leads to substantial unintended impacts when introduced species become invasive, causing environmental disturbance or transmitting diseases that affect people, livestock, other wildlife or the environment. Policy responses are usually only implemented after these species become established and damages are already incurred. International agreements to control trade are likewise usually based on selection of species with known impacts. We aim to further develop quantitative invasive species risk assessment for bird imports and extend the tool to explicitly address disease threats.LocationUnited States of America.MethodsWe use a two-step approach for rapid risk assessment based on the expected biological risks due to both the environmental and health impact of a potentially invasive wildlife species in trade. We assess establishment probability based on a model informed by historical observations and then construct a model of emerging infectious disease threat based on economic and ecological characteristics of the exporting country.ResultsWe illustrate how our rapid assessment tool can be used to identify high-priority species for regulation based on a combination of the threat they pose for becoming established and vectoring emerging infectious diseases.Main conclusionsOur approach can be executed for a species in a matter of days and is nested in an economic decision-making framework for determining whether the biological risk is justified by trade benefits

Molecular diversity among seven Solanum (eggplant and relatives) species assessed by simple sequence repeats (SSRs) markers

Seven Solanum species (eggplants) were investigated for molecular diversity. Besides its widespread cultivation, nutritional and economic importance, its genome has not been extensively researched. 39 Solanum accessions, a landrace and tomato variety (LBR 48) were molecularly analyzed by simple sequence repeat (SSR) marker technique. A dendrogram was obtained based on the Jaccard’s coefficient of similarity and unweighted pair group method with arithmetic mean (UPGMA) clustering. A total of 417 alleles were amplified with the number of alleles ranging from 5 (EM 141) to 38 (EM 120 b). Polymorphism was fairly high (0.05 to 0.92) among SSR markers with high number of repeats. Findings indicate that entries originating from different parts of the world did not form a distinct cluster, and there was no association between SSR marker pattern and geographical origin. SSR markers indicated a strong genetic affinity among S. viarum, S. melongena and S. aethiopicum Aculeatum group. Genetic relatedness between S. dasyphyllum and S. macrocarpon and between S. aethiopicum and S. macrocarpon are important for breeding. SSR markers assayed were informative for phylogenetic analysis; and have the potential to serve as perfect markers for studying variation. For plant breeders, close genetic relationships detected provide an avenue for introgression of high yielding and resistant genes into commercial and farmers’ varieties.Key words: Simple sequence repeats (SSR) markers, genetic diversity, polymorphism, multivariate analysis, Solanum species

Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells.

Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML

A drug utilization study of topical corticosteroids in the department of dermatology in a tertiary care teaching hospital in upper Assam

Background: Topical corticosteroids form an important group of drugs in dermatology and are among the most commonly prescribed medications. However, despite their efficacy, they are associated with various adverse effects and as majority of the skin conditions are chronic, there is a need to ensure that there is rationality in drug use. Thus, this study was conducted with an aim to analyze the drug utilization pattern of topical corticosteroids.Methods: The study was a hospital-based, prospective and observational study and conducted for a period of 12 months. The method of data collection was done based on one-on-one consultation with patients. Data collected were recorded prospectively in a specially designed proforma. Results were then entered and analyzed using Microsoft excel.Results: In the study, it was observed that 48% of the patients were males while 52% were females. Most patients belonged to the age group of 21-30 years (30%). Scabies (30%) was the most common dermatological condition. With regard to the prescribing frequency of different topical corticosteroids, mometasone furoate (31.4%) was the preferred choice in most patients. H1 antihistaminic drugs like levocetirizine (81.6%) were the most prescribed along with topical corticosteroids, followed by emollients (36.4%) and permethrin (29.2%). The average number of drugs per prescription was 3.6 and all drugs were prescribed by their generic names.Conclusions: Periodic monitoring of the drug utilization pattern in the form of prescription auditing is an effective tool to constitute guidelines for improving the utilization pattern

Testing for entanglement with periodic coarse-graining

Continuous variables systems find valuable applications in quantum information processing. To deal with an infinite-dimensional Hilbert space, one in general has to handle large numbers of discretized measurements in tasks such as entanglement detection. Here we employ the continuous transverse spatial variables of photon pairs to experimentally demonstrate novel entanglement criteria based on a periodic structure of coarse-grained measurements. The periodization of the measurements allows for an efficient evaluation of entanglement using spatial masks acting as mode analyzers over the entire transverse field distribution of the photons and without the need to reconstruct the probability densities of the conjugate continuous variables. Our experimental results demonstrate the utility of the derived criteria with a success rate in entanglement detection of $\sim60\%$ relative to $7344$ studied cases.Comment: V1: revtex4, 10 pages, 4 figures + supp. material (4 pages, 1 figure) V2: Substantial revisions implemented both in theory and experimental data analysi