Synthesis and evaluation of pyridylbenzofuran, pyridylbenzothiazole and pyridylbenzoxazole derivatives as ¹⁸F-PET imaging agents for β-amyloid plaques

The synthesis and SAR of new β-amyloid binding agents are reported. Evaluation of important properties for achieving good signal-to-background ratio is described. Compounds 27, 33, and 36 displayed desirable lipophilic and pharmacokinetic properties. Compound 27 was further evaluated with autoradiographic studies in vitro on human brain tissue and in vivo in Tg2576 mice. Compound 27 showed an increased signal-to-background ratio compared to flutemetamol 4, indicating its suitability as PET ligand for β-amyloid deposits in AD patients. The preparation of the corresponding (18)F-labeled PET radioligand of compound 27 is presented.     

The application of δ¹⁸O and δD for understanding water pools and fluxes in a Typha marsh

The δ¹⁸O and δD composition of water pools (leaf, root, standing water and soil water) and fluxes [transpiration (T), evaporation (E)] were used to understand ecohydrological processes in a managed Typha latifolia L. freshwater marsh. We observed isotopic steady‐state T and deep rooting in Typha. The isotopic mass balance of marsh standing water showed that E accounted for 3% of the total water loss, T accounted for 17% and subsurface drainage (D) accounted for the majority (80%). There was a vertical gradient in water vapour content and isotopic composition within and above the canopy sufficient for constructing an isotopic mass balance of water vapour during some sampling periods. During these periods, the proportion of T in evapotranspiration (T/ET) was between 56 ± 17% and 96 ± 67%, and the estimated error was relatively high (>37%) because of non‐local, background sources in vapour. Independent estimates of T/ET using eddy covariance measurements yielded similar mean values during the Typha growing season. The various T/ET estimates agreed that T was the dominant source of marsh vapour loss in the growing season. The isotopic mass balance of water vapour yielded reasonable results, but the mass balance of standing water provided more definitive estimates of water losses.     

Dual Δ¹³C/δ¹⁸O response to water and nitrogen availability and its relationship with yield in field-grown durum wheat

The combined use of stable carbon and oxygen isotopes in plant matter is a tool of growing interest in cereal crop management and breeding, owing to its relevance for assessing the photosynthetic and transpirative performance under different growing conditions including water and N regimes. However, this method has not been applied to wheat grown under real field conditions. Here, plant growth, grain yield (GY) and the associated agronomic components, carbon isotope discrimination (Δ¹³C) plus oxygen isotope composition (δ¹⁸O) as well as leaf and canopy gas exchange were measured in field‐grown wheat subjected to different water and N availabilities. Water limitation was the main factor affecting yield, leaf and canopy gas exchange and Δ¹³C and δ¹⁸O, whereas N had a smaller effect on such traits. The combination of Δ¹³C and δ¹⁸O gave a clear advantage compared with gas exchange measurements, as it provides information on the instantaneous and the long‐term plant photosynthetic and transpirative performance and are less labour intensive than gas exchange measurements. In addition, the combination of plant Δ¹³C and δ¹⁸O predicted differences in GY and related agronomical parameters, providing agronomists and breeders with integrative traits for selecting crop management practices and/or genotypes with better performance under water‐limiting and N‐limiting conditions.     

Modelling ¹⁸O₂ and ¹⁶O₂ unidirectional fluxes in plants: I. regulation of pre-industrial atmosphere

In closed systems, the O₂ compensation point (Γ_O) was previously defined as the upper limit of O₂ level, at a given CO₂ level, above which plants cannot have positive carbon balance and survive. Studies with ¹⁸O₂ measure the actual O₂ uptake by photorespiration due to the dual function of Rubisco, the enzyme that fixes CO₂ and takes O₂ as an alternative substrate. One-step modelling of CO₂ and O₂ uptakes allows calculating a plant specificity factor (Sp) as the sum of the biochemical specificity of Rubisco and a biophysical specificity, function of the resistance to CO₂ transfer from the atmosphere to Rubisco. The crossing points (Cx, Ox) are defined as CO₂ and O₂ concentrations for which O₂ and CO₂ uptakes are equal. It is observed that: (1) under the preindustrial atmosphere, photorespiration of C3 plants uses as much photochemical energy as photosynthesis, i.e. the Cx and Ox are equal or near the CO₂ and O₂ concentrations of that epoch; (2) contrarily to Γ_C, a Γ_O does not practically limit the plant growth, i.e. the plant net CO₂ balance is positive up to very high O₂ levels; (3) however, in a closed biosystem, Γ_O exists; it is not the limit of plant growth, but the equilibrium point between photosynthesis and the opposite respiratory processes; (4) a reciprocal relationship exists between Γ_O and Γ_C, as unique functions of the respective CO₂ and O₂ concentrations and of Sp, this invalidates some results showing two different functions for Γ_O and Γ_C, and, consequently, the associated analyses related to greenhouse effects in the past; (5) the pre-industrial atmosphere levels of O₂ and CO₂ are the Γ_O and Γ_C of the global bio-system. They are equal to or near the values of Cx and Ox of C3 plants, the majority of land plants in preindustrial period. We assume that the crossing points represent favourable feedback conditions for the biosphere-atmosphere equilibrium and could result from co-evolution of plants-atmosphere-climate. We suggest that the evolution of Rubisco and associated pathways is directed by an optimisation between photosynthesis and photorespiration.     

Modelling ¹⁸O₂ and ¹⁶O₂ unidirectional fluxes in plants: II. analysis of rubisco evolution

The studies of Rubisco characteristics observed during plant evolution show that the variation of the Rubisco specificity factor only improved by two times from cyanobacteria to modern C3 plants. However we note important variations of the ratio between the maximum rates of oxygenation and carboxylation (V_O/V_C). Modelling in vivo¹⁸O₂ data in plant gas exchange shows that the oxygenation reaction of Rubisco plays a regulating role when the photochemical energy exceeds the carboxylation capacity. A protective index ‘oxygenation capacity’ is postulated, related to the ratio V_O/V_C of Rubisco, and hence to the sink energy effect of photorespiration. Analysing the trends of Rubisco parameters along the evolutionary scale, we show: (1) the increase of both V_C and V_O; (2) the enhancement of CO₂ affinity; and (3) the rise in oxygenation capacity at the expense of the CO₂ specificity. Hence, the factors of evolutionary pressure have not only directed the enzyme towards a more efficient utilisation of CO₂, but mainly to positively use the unavoidable great loss of energy and assimilated carbon in the process of photorespiration. These observations reinforce the hypothesis of plant-atmosphere co-evolution and of the complex role of Rubisco, which seems to be selected to develop both better CO₂ affinity and oxygenation capacity. The latter increases the capacity of sink of photorespiration, in particular, during water stress or under high irradiance, the two conditions experienced by plants in terrestrial environments. These observations help to explain some handicaps of C4 plants, and the supremacy of CAM and C3 perennial higher plants in arid environments.     

Synthesis and in vivo evaluation of ¹⁸F-fluoroethyl GF120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters

The purpose of this study was to synthesize two new positron emission tomography (PET) probes, N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-[1?F]fluoroethoxy-9-oxo-4-acridine carboxamide ([1?F]3) and quinoline-3-carboxylic acid [2-(4-{2-[7-(2-[1?F]fluoroethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethyl}phenylcarbamoyl)-4,5-dimethoxyphenyl]amide ([1?F]4), and to evaluate the potential of these PET probes for assessing the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). [1?F]3 and [1?F]4 were synthesized by 1?F-alkylation of each O-desmethyl precursor with [1?F]2-fluoroethyl bromide for injection as PET probes. In vitro accumulation assay showed that treatment with P-gp/BCRP inhibitors (1 and 2) enhanced the intracellular accumulation capacity of P-gp- and BCRP-overexpressing MES-SA/Dx5 cells. In PET studies, the uptake (AUC(brain[0-)?? (min])) of [1?F]3 and [1?F]4 in wild-type mice co-injected with 1 were approximately sevenfold higher than that in wild-type mice, and the uptake of [1?F]3 and [1?F]4 in P-gp/Bcrp knockout mice were eight- to ninefold higher than that in wild-type mice. The increased uptake of [1?F]3 and [1?F]4 was similar to that of parent compounds ([11C]1 and [11C]2) previously described, indicating that radioactivity levels in the brain after injection of [1?F]3 and [1?F]4 are related to the function of drug efflux transporters. Also, these results suggest that the structural difference between parent compounds ([11C]1 and [11C]2) and fluoroethyl analogs ([1?F]3 and [1?F]4) do not obviously affect the potency against drug efflux transporters. In metabolite analysis of mice, the unchanged form in the brain and plasma at 60 min after co-injection of [1?F]4 plus 1 were higher (95% for brain; 81% for plasma) than that after co-injection of [1?F]3 plus 1. [1?F]4 is a promising PET probe to assess the function of drug efflux transporters.     

Sex, Death, and Evolution in Proto- and Metazoa, 1876–1913

In the period 1875–1920, a debate about the generality and applicability of evolutionary theory to all organisms was motivated by work on unicellular ciliates like Paramecium because of their peculiar nuclear dualism and life cycles. The French cytologist Emile Maupas and the German zoologist August Weismann argued in the 1880s about the evolutionary origins and functions of sex (which in the ciliates is not linked to reproduction), and death (which appeared to be the inevitable fate of lineages denied sexual conjugation), an argument rooted in the question of whether the ciliates and their processes where homologous to other cellular organisms. In the beginning of the twentieth century, this question of homology came to be less important as the ciliates were used by the British protozoologist Clifford Dobell and the American zoologist Herbert Spencer Jennings to study evolutionary processes in general rather than problems of development and cytology. For them, homology mattered less than analogy. This story illustrates two partially distinct problems in evolutionary biology: first, the question of whether all living things have common features and origins; and second, whether their history and current nature can be described by identical mechanisms. Where Maupas (contra Weismann) made the ciliates qualitatively the same as all other organisms in order to create a cohesive evolutionary theory for biology, Jennings and Dobell made them qualitatively different in order to achieve the same end. This revised version was published online in July 2006 with corrections to the Cover Date.     

Rates of entry and oxidation of acetate,glucose, d(?)-β-hydroxybutyrate,palmitate, oleate and stearate,and rates of production and oxidation of propionate and butyrate in fed and starved sheep

1. Rates of entry and oxidation of a range of metabolites have been measured in tracheostomized sheep (diet, 800g. of lucerne chaff and 100g. of maize/day) by combining isotope-dilution techniques with the continuous measurement of total respiratory gas exchange, and ¹⁴CO₂ production during the intravenous or intraruminal infusion of ¹⁴C-labelled substrates. 2. Mean entry rates in fed and starved (24hr.) sheep respectively, expressed as mg./min./kg. body wt.^0·75, were: glucose, 5·0 (range 4·8–5·1, 2 observations) and 3·8 (3·2–4·2, 4); acetate, 10·8 (9·1–13·5, 4) and 5·8 (1); d(−)-β-hydroxybutyrate, 1·4 (1) and 1·5 (0·8–2·4, 4); palmitate, oleate and stearate (starved sheep only) 1·0 (0·6–1·9, 7), 0·9 (0·2–1·6, 10) and 0·9 (0·5–1·1, 11) respectively. 3. Production rates of propionate and butyrate in continuously feeding sheep were 6·4 (4·7–8·3, 4) and 4·3 (3·4–6·1, 4) mg./min./kg.^0·75 respectively, and in starved (24hr.) sheep were 2·5 (2·2–2·9, 2) and 1·0 (0·8–1·2, 2) mg./min./kg.^0·75 respectively. 4. Calculated terminal values for the specific radioactivity of respiratory ¹⁴CO₂ during measurements of entry rates and production rates were used to calculate the contributions of individual substrates to overall oxidative metabolism. Mean values for fed and starved sheep respectively were: glucose, 9·1 (8·6–9·6, 2) and 11·2 (5·9–15·1, 4)%; acetate, 31·6 (26·8–38·1, 4) and 22·1 (1)%; d(−)-β-hydroxybutyrate, 10·4 (1) and 4·8 (1·9–7·7, 4)%; propionate, 23·0 (13·8–29·9, 4) and 7·1 (6·8–7·4, 2)%; butyrate, 16·5 (13·7–20·5, 4) and 5·3 (5·2–5·3, 2)%; palmitate, oleate and stearate (starved sheep only), 4·7 (2·0–7·7, 7), 4·0 (1·2–6·6, 10) and 4·4 (3·8–5·8, 9)% respectively. The sum of these values for individual substrates in fed and starved sheep, excluding that of β-hydroxybutyrate and after correction of the glucose value for the known interrelations of this substrate with propionate, accounted for 76% and 58% respectively of total production of carbon dioxide. 5. Calculations based on the proportion of substrate entry directly oxidized indicated that the substrates studied accounted for 63% (fed sheep) and 43% (starved sheep) of total energy expenditure measured by oxygen uptake. The contribution of β-hydroxybutyrate was excluded, and corrections were made for glucose–propionate interrelations, and for the different rates of oxidation of the methyl and carboxyl fragments of acetate. 6. The present results have been combined with those obtained earlier in this Laboratory to examine the relationships between rates of substrate entry and oxidation, and concentrations of substrate in blood. Rates of entry of acetate, glucose, d(−)-β-hydroxybutyrate, palmitate and oleate (but not stearate) were well correlated with concentration in blood, and substrate contribution to production of carbon dioxide showed a similar correlation to blood concentration, except with glucose. 7. It was concluded that the general technique is of potential value in providing valid quantitative parameters of animal metabolism.     

HIV and HCV： from Co-infection to Epidemiology, Transmission, Pathogenesis, and Treatment

Human immunodeficiency virus (HIV) is the infectious agent causing acquired immu-nodeficiency syndrome (AIDS),a deadliest scourge of human society. Hepatitis C virus (HCV) is a major causative agent of chronic liver disease and infects an estimated 170 million people worldwide,resulting in a serious public health burden. Due to shared routes of transmission,co-infection with HIV and HCV has become common among individuals who had high risks of blood exposures. Among hemophiliacs the co-infection rate accounts for 85%; while among injection drug users (IDU) the rate can be as high as 90%. HIV can accelerate the progression of HCV-related liver disease,particularly when immunodeficiency has developed. Although the effect of HCV on HIV infection is controversial,most studies showed an increase in mortality due to liver disease. HCV may act as a direct cofactor to fasten the progression of AIDS and decrease the tolerance of highly active antiretroviral therapy (HARRT). Conversely,HAART-related hepatotoxicity may enhance the progression of liver fibrosis. Due to above complications,co-infection with HCV and HIV-1 has imposed a critical challenge in the management of these patients. In this review,we focus on the epidemiology and transmission of HIV and HCV,the impact of the two viruses on each other,and their treatment.     

The Cell and Protoplasm as Container,Object, and Substance, 1835–1861

This article revisits the development of the protoplasm concept as it originally arose from critiques of the cell theory, and examines how the term “protoplasm” transformed from a botanical term of art in the 1840s to the so-called “living substance” and “the physical basis of life” two decades later. I show that there were two major shifts in biological materialism that needed to occur before protoplasm theory could be elevated to have equal status with cell theory in the nineteenth century. First, I argue that biologists had to accept that life could inhere in matter alone, regardless of form. Second, I argue that in the 1840s, ideas of what formless, biological matter was capable of dramatically changed: going from a “coagulation paradigm” (Pickstone, 1973) that had existed since Theophrastus, to a more robust conception of matter that was itself capable of movement and self-maintenance. In addition to revisiting Schleiden and Schwann’s original writings on cell theory, this article looks especially closely at Hugo von Mohl’s definition of the protoplasm concept in 1846, how it differed from his primordial utricle theory of cell structure two years earlier. This article draws on Lakoff and Johnson’s theory of “ontological metaphors” to show that the cell, primordial utricle, and protoplasm can be understood as material container, object, and substance, and that these overlapping distinctions help explain the chaotic and confusing early history of cell theory.     

Biosynthesis,isolation, purification and separation of nivalenol,fusarenone — X and zearalenone

Fusarium, graminearum KF 370 isolate is able to simultaneous biosynthesis of three toxic metabolites, namely: fusarenone-X (FUS), nivalenol (NIV) and zearalenone (F-2). After metabolites extraction with methanol — water (3:1) and defatting with n-heptane toxins were partitioned into chloroform layer. Purification of the? compounds was performed on Celite 545 — charcoal — Aluminiumoxid 90 column then metabolites were separated on Kieselgel 60 (200–300 mesh) column with developing solvent chloroform — methanol. This way FUS, NIV and F-2 were obtained as crystalline or high purity standards.     

When Do Allocations and Constructs Respect Material,Energy, Financial,and Production Balances in LCA and EEIO?

Conservation of mass and energy are essential to physical accounting, just as price and market balances are essential to economic accounting. These principles guide data collection and inventory compilation in industrial ecology. The resulting balanced surveys, however, can rarely be used directly for life cycle assessment (LCA) or environmentally extended input‐output (EEIO) analysis; some modeling is necessary to recast coproductions by multifunctional activities as monofunctional unit processes (a.k.a. Leontief production functions or technical “recipes”). This modeling is done with allocations in LCA and constructs in input‐output. In this article, we ask how these models respect or perturb the balances of the original inventory. Which allocations or constructs, applied to what type of data set, have the potential to simultaneously respect its multiple physical, financial, and market balances? Our analysis builds upon the recent harmonization of allocations and constructs and the ongoing development of multilayered supply and use inventory tables. We derive the necessary and sufficient conditions for balanced models, investigate the role of data aggregation, and clarify these models' relation to system expansion. We find that none of the modeling families in LCA and EEIO are balanced in general, but special data characteristics can allow for the respect of multiple balances. An analysis of these special cases allows for clear guidance for data compilation and methods integration.     

Partial sequence homologies between cytoskeletal proteins,c-myc,Rous sarcoma virus and adenovirus proteins,transducin, and β- and γ-crystallins

Computer based sequence comparisons indicate partial sequence homology between human c-myc, Rous sarcoma virus, adenovirus 7, and simian sarcoma virus proteins and the cytoskeletal proteins desmin, keratin and vimentin. In addition, sections of the oncogene proteins showed partial but significant homology to and subunits of transducin, -II and -BP crystallins showed partial but significant homology to the cytoskeletal proteins keratin, vimentin, desmin, and -tubulin, and to adenovirus 7 and simian sarcoma virus transforming gene proteins. -BP crystallin showed partial but significant homology to Rous sarcoma virus protein, and to and y subunits of transducin. Both crystallins showed partial sequence homology to the GTP-binding protein elongation factor TU fromEscherichia coli . These sequence homologies suggest a link between the mechanisms of normal lens cell differentiation, involving modifications to the cytoskeleton and subsequent changes to the pattern of protein synthesis, and mechanisms of neoplastic transformation. Furthermore the transducin-like region on -crystallin may be important for its interaction with lens membranes and the maintenance of short-range order for lens transparency.     

Pollen morphology and ultrastructure of Australian Monimiaceae ‐ Austromatthaea,Hedycarya, Kibara,Leviera, Steganthera and Tetrasynandra

The pollen morphology and ultrastructure of Austromatthaea elegans, Hedycarya angustifolia, H. loxocarya, Kibara rigidifolia, Leviera acuminata, Steganthera macooraia and Tetrasynandra laxiflora, are described. All are Australian members of the Monimiaceae sensu stricto of the order Laurales, subclass Magnoliidae. Except for Hedycarya angustifolia, which has pollen grains in permanent tetrads, all species have small, globose, apolar, inaperturate pollen. They can be identified under SEM by their surface ornamentation: Austromatthaea has fossulate sculpturing; Hedycarya angustifolia has tetrads with a warty configuration; H. loxocarya has echinate pollen; Kibara has spherical gemmae with nipple‐like projections; Leviera has stellate sculpturing; Steganthera has a verrucose surface with small spherical projections on each verruca, and Tetrasynandra is gemmate with one to several spiny projections on each gemma. The pollen grains of all genera of Australian Monimiaceae sensu stricto, some the results of previous studies, are summarized in tabular form. The exine has no columellae, foot layer or endexine, in contrast to the family Atherospermataceae (syn. subfamily Atherospermatoideae of the Monimiaceae, sensu lato). The most elaborate type of wall structure consists of radial elements ("radial processes") with white line‐centered regions extending from beyond the intine to the tectal region and a two‐layered intine with an outer channelled part (onciform zone). Trends of evolution from this type are discussed and comparisons are made with other Monimiaceae, Lauraceae, Amborellaceae and Trimeniaceae.     

Eicosanoids, β-cell function, and diabetes

Arachidonic acid (AA) is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes into eicosanoids, which are involved in diverse diseases, including type 1 and type 2 diabetes. During the last 30 years, evidence has been accumulated that suggests important functions for eicosanoids in the control of pancreatic β-cell function and destruction. AA metabolites of the COX pathway, especially prostaglandin E(2) (PGE(2)), appear to be significant factors to β-cell dysfunction and destruction, participating in the pathogenesis of diabetes and its complications. Several elegant studies have contributed to the sorting out of the importance of 12-LOX eicosanoids in cytokine-mediated inflammation in pancreatic β cells. The role of CYP eicosanoids in diabetes is yet to be explored. A recent publication has demonstrated that stabilizing the levels of epoxyeicosatrienoic acids (EETs), CYP eicosanoids, by inhibiting or deleting soluble epoxide hydrolase (sEH) improves β-cell function and reduces β-cell apoptosis in diabetes. In this review we summarize recent findings implicating these eicosanoid pathways in diabetes and its complications. We also discuss the development of animal models with targeted gene deletion and specific enzymatic inhibitors in each pathway to identify potential targets for the treatment of diabetes and its complications.