CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.
To evaluate the impact of single-nucleotide polymorphisms (SNPs) in CYP2C9, MDR1, SLCO1B1 and ABCG2 on the pharmacokinetics of fluvastatin in Chinese participants.A pharmacokinetic study of fluvastatin (single dose 40 mg) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of fluvastatin were determined by a high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by non-compartmental method. The SNPs were determined by TaqMan®(MGB) genotyping assay.Effect of CYP2C9*3 (c.1075A>C) on area under the plasma concentration-time curve (AUC) of fluvastatin was statistically significant. Heterozygous variant (C/A) carriers had higher AUC values compared to homozygous wild type (A/A) carriers (922.03±148.17 µg · h · L - 1 vs. 496.00±168.93 µg · h · L - 1, P=0.003092). The elimination half-life (T 1/2) values of fluvastatin were longer in MDR1 2677non-G carriers than in MDR1 2677G carriers (2.21±0.47 h vs. 1.25±0.62 h, P=0.02319), and also they were longer in MDR1 1236T-2677non-G-3435T carriers than in MDR1 1236C-2677G-3435C carriers (2.31±0.51 h vs. 1.32±0.62 h, P=0.03320). MDR1 C3435T polymorphism had a significant effect on maximal plasma concentrations (C max) of fluvastatin. Mutation gene T (TT+CT) carriers had higher C max values compared to homozygous wild type (C/C) carriers (688.54±142.67 µg · L - 1 vs. . 413.78±177.83 µg · L - 1, P=0.01448). Some SNPs such as MDR1 C1236T, ABCG2 c.34G>A, ABCG2 c.421C>A, SLCO1B1 c.388 A>G, SLCO1B1 c.521 T>C, SLCO1B1 c.571 T>C and SLCO1B1 c.597 C>T have no significant effects on fluvastatin pharmacokinetics.CYP2C9*3(1075A>C), MDR1 C3435T and MDR1 G2677T/A were determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.


SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc.
We have cloned a novel SOCS gene from Drosophila, socs36E, which is most homologous to the mammalian socs-5 gene. Socs36E is expressed zygotically, predominantly during embryogenesis, in a highly dynamic pattern. In vivo expression of SOCS36E in transgenic flies results in several adult phenotypes. Engrailed-GAL4 directed expression causes loss of the wing anterior cross vein, humeral outgrowths, absence of halteres and eye pigmentation defects. Expression of SOCS36E under apterous-GAL4 control resulted in outstretched wings. Full penetrance of these phenotypes required the presence of the SH2 and SOCS-box domains of SOCS36E. The observed phenotypes were consistent with defects in JAK/STAT or EGF-R signalling and were exacerbated in flies heterozygous for either the d-jak (hopscotch), d-stat (stat92E) or d-egf-r (der) genes. Conversely, inactivating one copy of the d-cbl gene, a negative regulator of the d-EGF-R, partially rescued the wing phenotypes. These genetic interactions imply that SOCS36E can suppress activities of the JAK/STAT and EGF-R signalling pathways in the wing disc and suggest that SOCS36E interacts with multiple pathways in vivo.


A 50 kDa protein present in conditioned medium of COLO-16 cells stimulates cell spreading and motility, and activates tyrosine phosphorylation of Neu/HER-2, in human SK-BR-3 mammary cancer cells.
A factor present in conditioned medium of COLO-16 human cancer cells causes fast spreading, fast plasma membrane ruffling, cell shape change, net translocation, stimulation of chemotaxis and growth arrest in human SK-BR-3 mammary cancer cells. Based on the spreading effect, the factor was purified to homogeneity and migrated as a 50 kDa protein in SDS-polyacrylamide gel electrophoresis. Addition of the purified 50 kDa factor to the target cells in culture results in tyrosine phosphorylation of the p185erbB2 receptor concomitant with a fast redistribution and clustering of the receptor. The 50 kDa factor is also specifically retained by affinity chromatography on the immobilized extracellular domain of p185erbB2. Antibodies directed against this domain also inhibit the induction of motility. These data suggest that the 50 kDa factor is a putative ligand of p185erbB2 in SK-BR-3 cells. Biochemical and immunological evidence further indicate that this factor differs from p185erbB2 ligands described so far. Its activity could play a role in the pathogenesis of breast cancer.


Two Members of the Aluminum-Activated Malate Transporter Family, SlALMT4 and SlALMT5, are Expressed during Fruit Development, and the Overexpression of SlALMT5 Alters Organic Acid Contents in Seeds in Tomato (Solanum lycopersicum).
The aluminum-activated malate transporter (ALMT) family of proteins transports malate and/or inorganic anions across plant membranes. To demonstrate the possible role of ALMT genes in tomato fruit development, we focused on SlALMT4 and SlALMT5, the two major genes expressed during fruit development. Predicted proteins were classified into clade 2 of the family, many members of which localize to endomembranes. Tissue-specific gene expression was determined using transgenic tomato expressing the β-glucuronidase reporter gene controlled by their own promoters. Both the genes were expressed in vascular bundles connecting to developing seeds in fruit and in the embryo of mature seeds. Further, SlALMT5 was expressed in embryo in developing seeds in fruit. Subcellular localization of both proteins to the endoplasmic reticulum (ER) was established by transiently expressing the green fluorescent protein fusions in plant protoplasts. SlALMT5 probably localized to other endomembranes as well. Localization of SlALMT5 to the ER was also confirmed by immunoblot analysis. The transport function of both SlALMT proteins was investigated electrophysiologically in Xenopus oocytes. SlALMT5 transported malate and inorganic anions such as nitrate and chloride, but not citrate. SlALMT4 also transported malate, but the results were less consistent perhaps because it did not localize strongly to the plasma membrane. To elucidate the physiological role of SlALMT5 further, we overexpressed SlALMT5 in tomato. Compared with the wild type, overexpressors exhibited higher malate and citrate contents in mature seeds, but not in fruit. We conclude that the malate transport function of SlALMT5 expressed in developing fruit influences the organic acid contents in mature seeds.


Calcification is not the Achilles' heel of cold-water corals in an acidifying ocean.
Ocean acidification is thought to be a major threat to coral reefs: laboratory evidence and CO2 seep research has shown adverse effects on many coral species, although a few are resilient. There are concerns that cold-water corals are even more vulnerable as they live in areas where aragonite saturation (Ωara ) is lower than in the tropics and is falling rapidly due to CO2 emissions. Here, we provide laboratory evidence that net (gross calcification minus dissolution) and gross calcification rates of three common cold-water corals, Caryophyllia smithii, Dendrophyllia cornigera, and Desmophyllum dianthus, are not affected by pCO2 levels expected for 2100 (pCO2 1058 μatm, Ωara 1.29), and nor are the rates of skeletal dissolution in D. dianthus. We transplanted D. dianthus to 350 m depth (pHT 8.02; pCO2 448 μatm, Ωara 2.58) and to a 3 m depth CO2 seep in oligotrophic waters (pHT 7.35; pCO2 2879 μatm, Ωara 0.76) and found that the transplants calcified at the same rates regardless of the pCO2 confirming their resilience to acidification, but at significantly lower rates than corals that were fed in aquaria. Our combination of field and laboratory evidence suggests that ocean acidification will not disrupt cold-water coral calcification although falling aragonite levels may affect other organismal physiological and/or reef community processes.


Electrochemical Selective and Simultaneous Detection of Diclofenac and Ibuprofen in Aqueous Solution Using HKUST-1 Metal-Organic Framework-Carbon Nanofiber Composite Electrode.
In this study, the detection protocols for the individual, selective, and simultaneous determination of ibuprofen (IBP) and diclofenac (DCF) in aqueous solutions have been developed using HKUST-1 metal-organic framework-carbon nanofiber composite (HKUST-CNF) electrode. The morphological and electrical characterization of modified composite electrode prepared by film casting was studied by scanning electronic microscopy and four-point-probe methods. The electrochemical characterization of the electrode by cyclic voltammetry (CV) was considered the reference basis for the optimization of the operating conditions for chronoamperometry (CA) and multiple-pulsed amperometry (MPA). This electrode exhibited the possibility to selectively detect IBP and DCF by simple switching the detection potential using CA. However, the MPA operated under optimum working conditions of four potential levels selected based on CV shape in relation to the potential value, pulse time, and potential level number, and order allowed the selective/simultaneous detection of IBP and DCF characterized by the enhanced detection performance. For this application, the HKUST-CNF electrode exhibited a good stability and reproducibility of the results was achieved.


Measuring Sexual Victimization: On What Fronts is the Jury Still Out and Do We Need it to Come In?
Rennison and Addington use National Crime Victimization Survey (NCVS) data to document the fact that college women experience violent victimization at a lower rate than women of the same age who do not attend college, which refutes the idea that women in college are at increased risk of being victimized. The measurement of victimization, especially sexual victimization, is, however, a topic that has be the source of much debate. Bureau of Justice Statistics is currently exploring what are the best methods for measuring sexual victimization within the NCVS, and recent methodological research, which is summarized in this article, could inform this process. Although consensus has seemingly been forming around come methods, such as using self-administered survey instruments and behaviorally specific questions when trying to measure sexual victimization, the jury is still out on some other design fronts. What is not clear is whether we need the jury to come in, so to speak. Some methodological variation might be acceptable, especially if the various methods being considered are producing similar results.


Functional synergy between Rab5 effector Rabaptin-5 and exchange factor Rabex-5 when physically associated in a complex.
Rab GTPases are central elements of the vesicular transport machinery. An emerging view is that downstream effectors of these GTPases are multiprotein complexes that include nucleotide exchange factors to ensure coupling between GTPase activation and effector function. We have previously shown that Rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of Rabex-5, a Rab5 nucleotide exchange factor, and the effector Rabaptin-5. We postulated that the physical association of these two proteins is necessary for their activity in Rab5-dependent endocytic membrane transport. To evaluate the functional implications of such complex formation, we have reconstituted it with the use of recombinant proteins and characterized its properties. First, we show that Rabaptin-5 increases the exchange activity of Rabex-5 on Rab5. Second, Rab5-dependent recruitment of Rabaptin-5 to early endosomes is completely dependent on its physical association with Rabex-5. Third, complex formation between Rabaptin-5 and Rabex-5 is essential for early endosome homotypic fusion. These results reveal a functional synergy between Rabaptin-5 and Rabex-5 in the complex and have implications for the function of analogous complexes for Rab and Rho GTPases.


Suppression of the tumorigenicity of B-16V melanoma cells via lysozyme gene.
The aim of this study was to evaluate the effects of lysozyme on the tumorigenicity of B-16V melanoma cells. After performing a series of molecular biology applications, including mRNA isolation, reverse transcriptase polymerase chain reaction, restriction digestions and ligations, recombinant pHM6 vector harboring mouse lysozyme gene (pHM6mLys) was constructed. B-16V melanoma cells were transfected with plasmid DNAs (pHM6 and pHM6mLys). Transfected cells (B-16VpHM6 and B-16VpHM6mLys) were selected in media containing geneticin. B-16V, B-16VpHM6, and B-16VpHM6mLys cells were then injected subcutaneously (s.c.) to the three groups of C57BL/6 inbred mice (30 mice/group). These mice were examined every 3 days for s.c. tumor development over 41 days. The results were evaluated by using statistical methods. Tumor formation was observed in all mice injected with B-16V and B-16VpHM6 cells in the first 8-12 days. However, tumor didn't develop in 16 of 30 of the mice injected with B-16VpHMmLys cells. Tumor-free animals (16 mice) in this group were reinjected with B-16V cells, and 9 of them died during the first 10 days of observation. Tumor development was not observed in the remaining 7 mice over 60 days of the experimental period. Results were statistically significant (p values < or = 0.05). These findings indicate that lysozyme expressed by B-16VpHMmLys cells may suppress the tumorigenicity of these cells and may help development of protective immunity against B-16V melanoma cells.


SALSA: A Novel Dataset for Multimodal Group Behavior Analysis.
Studying free-standing conversational groups (FCGs) in unstructured social settings (e.g., cocktail party ) is gratifying due to the wealth of information available at the group (mining social networks) and individual (recognizing native behavioral and personality traits) levels. However, analyzing social scenes involving FCGs is also highly challenging due to the difficulty in extracting behavioral cues such as target locations, their speaking activity and head/body pose due to crowdedness and presence of extreme occlusions. To this end, we propose SALSA, a novel dataset facilitating multimodal and Synergetic sociAL Scene Analysis, and make two main contributions to research on automated social interaction analysis: (1) SALSA records social interactions among 18 participants in a natural, indoor environment for over 60 minutes, under the poster presentation and cocktail party contexts presenting difficulties in the form of low-resolution images, lighting variations, numerous occlusions, reverberations and interfering sound sources; (2) To alleviate these problems we facilitate multimodal analysis by recording the social interplay using four static surveillance cameras and sociometric badges worn by each participant, comprising the microphone, accelerometer, bluetooth and infrared sensors. In addition to raw data, we also provide annotations concerning individuals' personality as well as their position, head, body orientation and F-formation information over the entire event duration. Through extensive experiments with state-of-the-art approaches, we show (a) the limitations of current methods and (b) how the recorded multiple cues synergetically aid automatic analysis of social interactions. SALSA is available at http://tev.fbk.eu/salsa.


RNA-seq based transcriptional map of bovine respiratory disease pathogen "Histophilus somni 2336".
Genome structural annotation, i.e., identification and demarcation of the boundaries for all the functional elements in a genome (e.g., genes, non-coding RNAs, proteins and regulatory elements), is a prerequisite for systems level analysis. Current genome annotation programs do not identify all of the functional elements of the genome, especially small non-coding RNAs (sRNAs). Whole genome transcriptome analysis is a complementary method to identify "novel" genes, small RNAs, regulatory regions, and operon structures, thus improving the structural annotation in bacteria. In particular, the identification of non-coding RNAs has revealed their widespread occurrence and functional importance in gene regulation, stress and virulence. However, very little is known about non-coding transcripts in Histophilus somni, one of the causative agents of Bovine Respiratory Disease (BRD) as well as bovine infertility, abortion, septicemia, arthritis, myocarditis, and thrombotic meningoencephalitis. In this study, we report a single nucleotide resolution transcriptome map of H. somni strain 2336 using RNA-Seq method.The RNA-Seq based transcriptome map identified 94 sRNAs in the H. somni genome of which 82 sRNAs were never predicted or reported in earlier studies. We also identified 38 novel potential protein coding open reading frames that were absent in the current genome annotation. The transcriptome map allowed the identification of 278 operon (total 730 genes) structures in the genome. When compared with the genome sequence of a non-virulent strain 129Pt, a disproportionate number of sRNAs (∼30%) were located in genomic region unique to strain 2336 (∼18% of the total genome). This observation suggests that a number of the newly identified sRNAs in strain 2336 may be involved in strain-specific adaptations.


Impact of complex surfaces on biomicrorheological measurements using optical tweezers.
The characterisation of physical properties in biologically relevant processes and the development of novel microfluidic devices for this purpose are experiencing a great resurgence at present. In many of measurements of this type where a probe in a fluid is used, the strong influence of the boundaries of the volume used is a serious problem. In these geometries the proximity of a probe to a wall can severely influence the measurement. However, although much knowledge has been gained about flat walls, to date, the effect of non-planar surfaces at microscopic scale on rotational motion of micro-objects has not been studied. Here we present for the first time both experimental measurements and numerical computations which aim to study the drag torque on optically trapped rotating particles moving near 3D-printed conical and cylindrical walls on-chip. These results are essential for quantifying how curved walls can effect the torque on particles, and thus enable accurate hydrodynamic simulations at the micron-scale. This opens the potential for new sensing approaches under more complex conditions, allowing both dynamic and microrheological studies of biological systems and lab-on-chip devices.


The importance of kinetics and redox in the biogeochemical cycling of iron in the surface ocean.
It is now well established that Iron (Fe) is a limiting element in many regions of the open ocean. Our current understanding of the key processes which control iron distribution in the open ocean have been largely based on thermodynamic measurements performed under the assumption of equilibrium conditions. Using this equilibrium approach, researchers have been able to detect and quantify organic complexing ligands in seawater and examine their role in increasing the overall solubility of iron. Our current knowledge about iron bioavailability to phytoplankton and bacteria is also based heavily on carefully controlled laboratory studies where it is assumed the chemical species are in equilibrium in line with the free ion association model and/or its successor the biotic ligand model. Similarly most field work on iron biogeochemistry generally consists of a single profile which is in essence a "snap-shot" in time of the system under investigation. However it is well known that the surface ocean is an extremely dynamic environment and it is unlikely if thermodynamic equilibrium between all the iron species present is ever truly achieved. In sunlit waters this is mostly due to the daily passage of the sun across the sky leading to photoredox processes which alter Fe speciation by cycling between redox states and between inorganic and organic species. Episodic deposition events, dry and wet, are also important perturbations to iron cycling as they bring in new iron to the system and alter the equilibrium between iron species and phases. Here we utilize new field data collected in the open ocean on the complexation kinetics of iron in the surface ocean to identify the important role of weak iron binding ligands (i.e., those that cannot maintain iron in solution indefinitely at seawater pH: α(FeL) < α(Fe)') in allowing transient increases in iron solubility in response to iron deposition events. Experiments with the thermal [Formula: see text] source SOTS-1 also indicate the short term impact of this species on iron solubility also with relevance to the euphotic zone. This data highlights the roles of kinetics, redox, and weaker iron binding ligands in the biogeochemical cycling of iron in the ocean.


Fundamental niche prediction of the pathogenic yeasts Cryptococcus neoformans and Cryptococcus gattii in Europe.
Fundamental niche prediction of Cryptococcus neoformans and Cryptococcus gattii in Europe is an important tool to understand where these pathogenic yeasts have a high probability to survive in the environment and therefore to identify the areas with high risk of infection. In this study, occurrence data for C. neoformans and C. gattii were compared by MaxEnt software with several bioclimatic conditions as well as with soil characteristics and land use. The results showed that C. gattii distribution can be predicted with high probability along the Mediterranean coast. The analysis of variables showed that its distribution is limited by low temperatures during the coldest season, and by heavy precipitations in the driest season. C. neoformans var. grubii is able to colonize the same areas of C. gattii but is more tolerant to cold winter temperatures and summer precipitations. In contrast, the C. neoformans var. neoformans map was completely different. The best conditions for its survival were displayed in sub-continental areas and not along the Mediterranean coasts. In conclusion, we produced for the first time detailed prediction maps of the species and varieties of the C. neoformans and C. gattii species complex in Europe and Mediterranean area.


Free Radical Imaging Using In Vivo Dynamic Nuclear Polarization-MRI.
Redox reactions that generate free radical intermediates are essential to metabolic processes, and their intermediates can produce reactive oxygen species, which may promote diseases related to oxidative stress. The development of an in vivo electron spin resonance (ESR) spectrometer and its imaging enables us noninvasive and direct measurement of in vivo free radical reactions in living organisms. The dynamic nuclear polarization magnetic resonance imaging (DNP-MRI), also called PEDRI or OMRI, is also a new imaging method for observing free radical species in vivo. The spatiotemporal resolution of free radical imaging with DNP-MRI is comparable with that in MRI, and each of the radical species can be distinguished in the spectroscopic images by changing the frequency or magnetic field of ESR irradiation. Several kinds of stable nitroxyl radicals were used as spin probes to detect in vivo redox reactions. The signal decay of nitroxyl probes, which is determined with in vivo DNP-MRI, reflects the redox status under oxidative stress, and the signal decay is suppressed by prior administration of antioxidants. In addition, DNP-MRI can also visualize various intermediate free radicals from the intrinsic redox molecules. This noninvasive method, in vivo DNP-MRI, could become a useful tool for investigating the mechanism of oxidative injuries in animal disease models and the in vivo effects of antioxidant drugs.


Preparation and X-ray crystal study of benziodoxaborole derivatives: new hypervalent iodine heterocycles.
A series of heterocyclic compounds containing trivalent iodine, oxygen, and boron in a five-membered ring were prepared and structurally investigated by X-ray crystallography. 1-Chloro-4-fluoro-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol was synthesized by chlorination of 2-fluoro-6-iodophenylboronic acid followed by treatment of the intermediate iododichloride with water. 1-Acetoxy-4-fluoro-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol, 1-acetoxy-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol, and similar 1-substituted trifluoroacetate derivatives of benziodoxaborole were prepared the hypochlorite oxidation of 2-fluoro-6-iodophenylboronic acid or 2-iodophenylboronic acid in acetic or trifluoroacetic acid, respectively. 1-Acetoxy substituted benziodoxaborole can be further converted to the respective trifluoroacetate by treatment with trifluoroacetic acid or to the 1-hydroxy derivative by basic hydrolysis with aqueous NaHCO(3). X-ray structural studies of 1-chloro- and 1-trifluoroacetoxy substituted benziodoxaboroles 13, 17, and 18 have shown the presence of a planar five-membered heterocyclic ring with unusually short endocyclic I-O bond distance of 2.04-2.09 Å. Slow crystallization of 4-fluoro-1-trifluoroacetoxy-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol from methanol resulted in the formation of a tetrameric macrocyclic structure 21 resulting from self-assembly of the initially formed 4-fluoro-1,3-dimethoxy-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol. Structural parameters of the five-membered iodoxoborol ring, such as the planar geometry and the short B-O and O-I bonds lengths in 13, 17, and 18 compared to those in 21 and known benziodoxoles are indicative of partially aromatic character of this ring. Density functional theory (DFT) predicted NIST (0) and NIST (1) indexes for 1-chloro- and 1-trifluoroacetoxy substituted benziodoxaboroles, however, are indicative of significantly lower aromaticity compared to the classic aromatic systems.


APC in cell migration.
Adenomatous Polyposis Coli (APC) is a tumor suppressor protein involved in the initiation and progression of colon cancer. The most widely accepted function ofAPC is to participate to the Wnt signaling pathway, by downregulating beta-catenin and thereby controlling gene transcription and cell proliferation. However, APC is clearly a multifunctional protein whose loss contributes to tumor formation in multiple ways. Regulation of APC localization during cell migration and the ability of APC to bind multiple polarity proteins and microtubule-associated molecules support the idea that APC plays a key role in directed cell migration and that this function may contribute to its tumour suppressor activity.


A time-motion study of registered nurses' workflow in intensive care unit remote monitoring.
Utilizing advanced information technology, Intensive Care Unit (ICU) remote monitoring allows highly trained specialists to oversee a large number of patients at multiple sites on a continuous basis. In the current research, we conducted a time-motion study of registered nurses' work in an ICU remote monitoring facility. Data were collected on seven nurses through 40 hours of observation. The results showed that nurses' essential tasks were centered on three themes: monitoring patients, maintaining patients' health records, and managing technology use. In monitoring patients, nurses spent 52% of the time assimilating information embedded in a clinical information system and 15% on monitoring live vitals. System-generated alerts frequently interrupted nurses in their task performance and redirected them to manage suddenly appearing events. These findings provide insight into nurses' workflow in a new, technology-driven critical care setting and have important implications for system design, work engineering, and personnel selection and training.


Sexually transmitted infections after bereavement - a population-based cohort study.
Loss of a loved one has consistently been associated with various health risks. Little is however known about its relation to sexually transmitted infections (STIs). We conducted a population-based cohort study during 1987-2012 using the Swedish Multi-Generation Register, including 3,002,209 women aged 10-44 years. Bereavement was defined as death of a child, parent, sibling or spouse (N = 979,579, 33 %). STIs were defined as hospital visits with an STI as main or secondary diagnosis. Poisson regression and negative binomial regression were used to estimate incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) of STIs, comparing incidence rates of women who had experienced loss to those who had not. Bereaved women were at significantly higher risk of nearly all STIs studied. The relative risk of any STI was highest during the first year after loss (IRR: 1.45, 95 % CI: 1.27-1.65) and predominantly among women with subsequent onset of psychiatric disorders after bereavement (IRR: 2.61, 95 % CI: 2.00-3.34). Notably, a consistent excess risk, persisting for over five years, was observed for acute salpingitis (IRR: 1.28, 95 % CI: 1.13-1.44), a severe complication of bacterial STIs. These data suggest that women who have experienced bereavement are at increased risk of STIs.


The relationship between crown size and ring width in Pinus sylvestris L. stems: dependence on indole-3-acetic acid, carbohydrates and nitrogen in the cambial region.
Indole-3-acetic acid (IAA), carbohydrates, total nitrogen and amino acids in the cambial region and bark were measured at the top (10-year-old internode) and bottom (1.3 m) of the main stem of 50-year-old Pinus sylvestris L. trees, having different rates and longitudinal gradients of annual ring width formation. The trees were sampled during the most active period of wood production (June 23, July 15) and at the end of this period (August 23). Trees with a small crown and relatively slow growth rate (S-trees) were compared with trees in the same stand that had a large crown and fast growth rate (F-trees) as a result of thinning and fertilization. The effect of bottom pruning fast-growing trees (pruned F-trees) was also investigated. The F-trees had greater wood production than the S-trees at both the stem top and bottom. The difference was larger at the stem bottom, thus the relative decrease in ring width down the stem was steeper in the S-trees. The amount of sucrose and IAA per cm(2) in cambial region tissues was higher in F-trees than in S-trees. However, the differences in annual ring width between treatments and within trees were not reflected in the concentrations (expressed per gram fresh weight) of these substances, measured either in differentiating xylem, the cambium plus phloem, or in the cambial region as a whole. The concentrations of total nitrogen and amino acids were slightly higher in the F-trees than in the S-trees. Pruning the F-trees reduced wood production, particularly at the stem bottom, inhibited the springtime increase in starch, and decreased the amounts of sucrose and IAA per cm(2) in the cambial region. However, it was evident that the concentrations of sucrose, IAA, amino acid and nitrogen in the cambial region were not related to ring width. During June and July, the concentrations of these substances were generally higher at the stem bottom in the pruned F-trees than in the F-trees. The results provide evidence that it is the activity of the cambium rather than the availability of carbohydrates that determines the allocation of wood production along the tree stem. The results also indicate that tracheid production is not directly related to the IAA concentration in the cambial region.


Decreased bacteria activity on Si₃N₄ surfaces compared with PEEK or titanium.
A significant need exists for orthopedic implants that can intrinsically resist bacterial colonization. In this study, three biomaterials that are used in spinal implants--titanium (Ti), polyether-ether-ketone (PEEK), and silicon nitride (Si₃N₄)--were tested to understand their respective susceptibility to bacterial infection with Staphylococcus epidermidis, Staphlococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus. Specifically, the surface chemistry, wettability, and nanostructured topography of respective biomaterials, and the effects on bacterial biofilm formation, colonization, and growth were investigated. Ti and PEEK were received with as-machined surfaces; both materials are hydrophobic, with net negative surface charges. Two surface finishes of Si₃N₄ were examined: as-fired and polished. In contrast to Ti and PEEK, the surface of Si₃N₄ is hydrophilic, with a net positive charge. A decreased biofilm formation was found, as well as fewer live bacteria on both the as-fired and polished Si₃N₄. These differences may reflect differential surface chemistry and surface nanostructure properties between the biomaterials tested. Because protein adsorption on material surfaces affects bacterial adhesion, the adsorption of fibronectin, vitronectin, and laminin on Ti, PEEK, and Si₃N₄ were also examined. Significantly greater amounts of these proteins adhered to Si₃N₄ than to Ti or PEEK. The findings of this study suggest that surface properties of biomaterials lead to differential adsorption of physiologic proteins, and that this phenomenon could explain the observed in-vitro differences in bacterial affinity for the respective biomaterials. Intrinsic biomaterial properties as they relate to resistance to bacterial colonization may reflect a novel strategy toward designing future orthopedic implants.


The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial.
Serial measurements of anti-double-stranded DNA (anti-dsDNA) and complement are routine in the management of systemic lupus erythematosus (SLE), but their utility as biomarkers in preemptive treatment to prevent flares remains a subject of controversy. We hypothesized that concomitant elevation of anti-dsDNA and C3a can predict SLE activity in patients with stable or inactive disease and that short-term treatment with corticosteroids can avert flares. In this prospective, randomized, double-blind, placebo-controlled trial, 154 patients were evaluated monthly for up to 18 months, with measurements of C3a, C3, C4, CH50, and anti-dsDNA levels. Patients who remained clinically stable but showed serologic evidence of an SLE flare (elevation of both the anti-dsDNA level by 25% and the C3a level by 50% over the previous 1-2 monthly visits) were randomized to receive either prednisone or placebo therapy at a dosage of 30 mg/day for 2 weeks, 20 mg/day for 1 week, and 10 mg/day for 1 week. Forty-one patients (21 randomized to prednisone and 20 randomized to placebo) experienced a serologic flare. Analysis of severe flares occurring <or=90 days from randomization revealed that 6 occurred in patients taking placebo and none occurred in patients taking prednisone (P = 0.007). Severe flares resulted in an increase in the prednisone dosage to >40 mg/day and/or the addition of an immunosuppressive agent. Furthermore, improvement in scores on the Systemic Lupus Erythematosus Disease Activity Index, decreased levels of anti-dsDNA antibodies, and increased levels of C4 occurred 1 month after initiation of prednisone treatment. These preliminary data support our hypothesis that in a subset of clinically stable SLE patients with a combination of elevated C3a and anti-dsDNA levels, short-term corticosteroid therapy may avert a severe flare.


Adaptive supersensitivity in the guinea pig vas deferens is associated with a reduction in the abundance of the alpha 2 subunit isoform of Na+/K(+)-ATPase.
Adaptive supersensitivity has been demonstrated previously in the guinea pig vas deferens after chronic treatment with reserpine, postganglionic denervation, or preganglionic denervation. The magnitude of the change in sensitivity was similar regardless of the method of induction; the underlying mechanism was identified as a partial depolarization secondary to reduced activity of the Na+/K+ pump. Experiments were conducted to quantitatively determine whether the identified losses in Na+/K(+)-ATPase activity and [3H]ouabain binding were due to reductions in the levels of specific protein subunits of the sodium pump. Electrophoretic separation and quantification of the abundance of alpha subunit isoforms were accomplished using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and slot blot analysis. Supersensitivity was induced in the guinea pig vas deferens through pretreatment with reserpine (1.0 mg/kg/day x 5 days). The abundance of the alpha 2 subunit isoform was reduced by 41% in tissue homogenates obtained from animals treated with reserpine, compared with untreated controls. In contrast, there was no significant alteration in the alpha 1 subunit isoform (a protein similar in size to that previously identified in vascular smooth muscle as a "truncated" form of the protein). These data suggest that the adaptation of the guinea pig vas deferens after a chronic reduction in net stimulus is mediated through a change in a specific cellular protein. This evidence supports the assignment of the alpha 2 subunit isoform as the specific protein responsible for the development of nonspecific adaptive supersensitivity in the guinea pig vas deferens.


Antimicrobial Properties of Gallium(III)- and Iron(III)-Loaded Polysaccharides Affecting the Growth of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, In Vitro.
Antimicrobial resistance (AMR) has become a global concern as many bacterial species have developed resistance to commonly prescribed antibiotics, making them ineffective to treatments. One type of antibiotics, gallium(III) compounds, stands out as possible candidates due to their unique "Trojan horse" mechanism to tackle bacterial growth, by substituting iron(III) in the metabolic cycles of bacteria. In this study, we tested three polysaccharides (carboxymethyl cellulose (CMC), alginate, and pectin) as the binding and delivery agent for gallium on three bacteria (Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus) with a potential bioresponsive delivery mode. Two types of analysis on bacterial growth (minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC)) were carried out while iron(III)-loaded polysaccharide samples were also tested for comparison. The results suggested that gallium showed an improved inhibitory activity on bacterial growth, in particular gallium(III)-loaded carboxymethyl cellulose (Ga-CMC) sample showing an inhibiting effect on growth for all three tested bacteria. At the MIC for all three bacteria, Ga-CMC showed no cytotoxicity effect on human dermal neonatal fibroblasts (HDNF). Therefore, these bioresponsive gallium(III) polysaccharide compounds show significant potential to be developed as the next-generation antibacterial agents with controlled release capability.


Effects of alpha-carbon substituents on the N-demethylation of N-methyl-2-phenethylamines by rat liver microsomes.
The effects of methyl, ethyl, isopropyl, isobutyl, and benzyl substituents at the alpha-carbon of N-methyl-2-phenethylamine on the kinetics of its N-demethylation in liver microsomes from both control and phenobarbital pretreated rats were studied. In control microsomes, the kinetic studies indicated that more than one enzyme was active for N-demethylation of N-methyl-alpha-methylphenethylamine (methamphetamine) while the other N-methyl-2-phenethylamines appeared to be demethylated by a single enzyme. In microsomes from phenobarbital pretreated animals, there appeared to be more than one enzyme system which was active for N-demethylation of all compounds except N-methyl-alpha-benzylphenethylamine. One of these had a much higher affinity for alpha-ethyl, isopropyl, and isobutyl N-methylphenethylamines while another exhibited affinities for substrates similar to the constitutive enzyme in control microsomes. A correlation was observed between the octanol-buffer or heptane-buffer distribution ratios of the compounds and the negative logarithm of the Michaelis constant (pKm) for the enzyme in control microsomes and for each of the enzyme systems in microsomes from phenobarbital-pretreated animals. Therefore, it is indicated that the concentration of a substrate at the active site of these microsomal enzymes is a function of its lipid solubility.


Medication use for low back pain in primary care.
A longitudinal observational study of primary care patients with low back pain. 1) To describe medications prescribed for back pain, 2) to identify patient characteristics associated with type of drug therapy, 3) to determine if the prescription of certain drugs is associated with better outcomes, and 4) to compare physician prescribing behavior with national guidelines. Few previous studies have focused on medication prescribing patterns for back pain in primary care. Two-hundred nineteen patients aged 20-69 years who were making a first visit for an episode of back pain were studied. After the visit, patients completed questionnaires regarding sociodemographic characteristics, health status, back pain experience, and use of medications. Symptom severity and dysfunction were assessed by telephone 1 week after the visit. Sixty-nine percent of patients were prescribed nonsteroidal anti-inflammatory drugs, 35% muscle relaxants, 12% narcotics, and 4% acetaminophen. Twenty percent received no medications. Patients were more likely to receive medications if they had a desire for medication, pain below the knee, less than 3 weeks of pain before visit, more severe symptoms, or greater dysfunction. Patients with more severe symptoms were more likely to receive narcotics or muscle relaxants. Patients with greater dysfunction were also more likely to receive narcotics. Type of drug therapy predicted symptom severity but not dysfunction after 1 week. Controlling for other factors, those receiving medications had less severe symptoms after 1 week than patients who received no medication. Patients receiving both muscle relaxants and nonsteroidal anti-inflammatory drugs had the best outcomes. Medication use for back pain in this health maintenance organization was generally concordant with national guidelines. Nonsteroidal anti-inflammatory drugs, often augmented by muscle relaxants, are a standard medical treatment for back pain in primary care. In this observational study, patients prescribed medications, particularly muscle relaxants, reported less severe symptoms after 1 week than those receiving no medications. However, randomized trials are needed to determine which medication or combinations of medications are most effective.


Ultra-high contrast retinal display system for single photoreceptor psychophysics.
Due to the enormous dynamic range of human photoreceptors in response to light, studying their visual function in the intact retina challenges the stimulation hardware, specifically with regard to the displayable luminance contrast. The adaptive optics scanning laser ophthalmoscope (AOSLO) is an optical platform that focuses light to extremely small retinal extents, approaching the size of single photoreceptor cells. However, the current light modulation techniques produce spurious visible backgrounds which fundamentally limit experimental options. To remove unwanted background light and to improve contrast for high dynamic range visual stimulation in an AOSLO, we cascaded two commercial fiber-coupled acousto-optic modulators (AOMs) and measured their combined optical contrast. By compensating for zero-point differences in the individual AOMs, we demonstrate a multiplicative extinction ratio in the cascade that was in accordance with the extinction ratios of both single AOMs. When latency differences in the AOM response functions were individually corrected, single switch events as short as 50 ns with radiant power contrasts up to 1:1010 were achieved. This is the highest visual contrast reported for any display system so far. We show psychophysically that this contrast ratio is sufficient to stimulate single foveal photoreceptor cells with small and bright enough visible targets that do not contain a detectable background. Background-free stimulation will enable photoreceptor testing with custom adaptation lights. Furthermore, a larger dynamic range in displayable light levels can drive photoreceptor responses in cones as well as in rods.


Navigating the complexity of ecological stability.
Human actions challenge nature in many ways. Ecological responses are ineluctably complex, demanding measures that describe them succinctly. Collectively, these measures encapsulate the overall 'stability' of the system. Many international bodies, including the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, broadly aspire to maintain or enhance ecological stability. Such bodies frequently use terms pertaining to stability that lack clear definition. Consequently, we cannot measure them and so they disconnect from a large body of theoretical and empirical understanding. We assess the scientific and policy literature and show that this disconnect is one consequence of an inconsistent and one-dimensional approach that ecologists have taken to both disturbances and stability. This has led to confused communication of the nature of stability and the level of our insight into it. Disturbances and stability are multidimensional. Our understanding of them is not. We have a remarkably poor understanding of the impacts on stability of the characteristics that define many, perhaps all, of the most important elements of global change. We provide recommendations for theoreticians, empiricists and policymakers on how to better integrate the multidimensional nature of ecological stability into their research, policies and actions.


Beyond a Passive Conduit: Implications of Lymphatic Biology for Kidney Diseases.
The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease.


What is a moment? "Cortical" sensory integration over a brief interval.
Recognition of complex temporal sequences is a general sensory problem that requires integration of information over time. We describe a very simple "organism" that performs this task, exemplified here by recognition of spoken monosyllables. The network's computation can be understood through the application of simple but generally unexploited principles describing neural activity. The organism is a network of very simple neurons and synapses; the experiments are simulations. The network's recognition capabilities are robust to variations across speakers, simple masking noises, and large variations in system parameters. The network principles underlying recognition of short temporal sequences are applied here to speech, but similar ideas can be applied to aspects of vision, touch, and olfaction. In this article, we describe only properties of the system that could be measured if it were a real biological organism. We delay publication of the principles behind the network's operation as an intellectual challenge: the essential principles of operation can be deduced based on the experimental results presented here alone. An interactive web site (http://neuron.princeton.edu/ approximately moment) is available to allow readers to design and carry out their own experiments on the organism.


Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors.
Single-cell mouse embryos were infected in vitro with recombinant lentiviral vectors to generate transgenic mice carrying the green fluorescent protein (GFP) gene driven by a ubiquitously expressing promoter. Eighty percent of founder mice carried at least one copy of the transgene, and 90% of these expressed GFP at high levels. Progeny inherited the transgene(s) and displayed green fluorescence. Mice generated using lentiviral vectors with muscle-specific and T lymphocyte-specific promoters expressed high levels of GFP only in the appropriate cell types. We have also generated transgenic rats that express GFP at high levels, suggesting that this technique can be used to produce other transgenic animal species.


Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis.
Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome.


The genetic association of RUNX3 with ankylosing spondylitis can be explained by allele-specific effects on IRF4 recruitment that alter gene expression.
To identify the functional basis for the genetic association of single nucleotide polymorphisms (SNP), upstream of the RUNX3 promoter, with ankylosing spondylitis (AS). We performed conditional analysis of genetic association data and used ENCODE data on chromatin remodelling and transcription factor (TF) binding sites to identify the primary AS-associated regulatory SNP in the RUNX3 region. The functional effects of this SNP were tested in luciferase reporter assays. Its effects on TF binding were investigated by electrophoretic mobility gel shift assays and chromatin immunoprecipitation. RUNX3 mRNA levels were compared in primary CD8+ T cells of AS risk and protective genotypes by real-time PCR. The association of the RUNX3 SNP rs4648889 with AS (p<7.6×10(-14)) was robust to conditioning on all other SNPs in this region. We identified a 2 kb putative regulatory element, upstream of RUNX3, containing rs4648889. In reporter gene constructs, the protective rs4648889 'G' allele increased luciferase activity ninefold but significantly less activity (4.3-fold) was seen with the AS risk 'A' allele (p≤0.01). The binding of Jurkat or CD8+ T-cell nuclear extracts to the risk allele was decreased and IRF4 recruitment was reduced. The AS-risk allele also affected H3K4Me1 histone methylation and associated with an allele-specific reduction in RUNX3 mRNA (p<0.05). We identified a regulatory region upstream of RUNX3 that is modulated by rs4648889. The risk allele decreases TF binding (including IRF4) and reduces reporter activity and RUNX3 expression. These findings may have important implications for understanding the role of T cells and other immune cells in AS.


Comparison of no-prior and soft-prior regularization in biomedical microwave imaging.
Microwave imaging for medical applications is attractive because the range of dielectric properties of different soft tissues can be substantial. Breast cancer detection and monitoring of treatment response are areas where this technology could be important because of the contrast between normal and malignant tissue. Unfortunately, the technique is unable to achieve the high spatial resolution at depth in tissue which is available from other conventional modalities such as x-ray computed tomography (CT) or magnetic resonance imaging (MRI). We have incorporated a soft-prior regularization strategy within our microwave reconstruction algorithm and compared it with the images obtained with traditional no-prior (Levenberg-Marquardt) regularization. Initial simulation and phantom results show a significant improvement of the recovered electrical properties. Specifically, errors in the microwave property estimates were improved by as much as 95%. The effects of a false-inclusion region were also evaluated and the results show that a small residual property bias of 6% in permittivity and 15% in conductivity can occur that does not otherwise degrade the property recovery accuracy of inclusions that actually exist. The work sets the stage for integrating microwave imaging with MR for improved resolution and functional imaging of the breast in the future.


A comparison of cervical histopathology variability using whole slide digitized images versus glass slides: experience with a statewide registry.
Whole slide imaging is increasingly used for primary and consultative diagnoses, teaching, telepathology, slide sharing, and archiving. We compared pathologist evaluations of glass slides and corresponding digitized images within the context of a statewide surveillance effort. Cervical specimens collected by the New Mexico HPV Pap Registry research program targeted cases diagnosed between 2006 and 2010. Two samples of 250 slides each were digitized with the ScanScope XT (Aperio, Vista, CA) microscope and reviewed with Aperio ImageScope reader. (1) A "random set" had a distribution of community diagnoses: 70% from cases of cervical intraepithelial neoplasia grade 2 or higher, 20% from cases of cervical intraepithelial neoplasia grade 1 and 10% from negative cases. (2) A "discrepant set" was represented by difficult cases where 2 study pathologists initially disagreed. Within the regular workflow of the New Mexico HPV Pap Registry, 3 pathologists read the slides 2 to 3 times each without knowledge of clinical history, previous readings or sampling scheme. Pathologists also read each corresponding image twice. For within- and between-reader comparisons we calculated unweighted κ statistics and asymmetry χ(2) tests. Across all comparisons, slides and images yielded similar results. For the random set, almost all within-reader and between-reader Kappa values ranged between 0.7 and 0.8 and 0.6 and 0.7, respectively. For the discrepant set, most within- and between-reader κ values were 0.4 to 0.6. As cervical intraepithelial neoplasia diagnostic terminology changes, pathologists may need to re-read histopathology slides to compare disease trends over time, eg, before/after introduction of human papillomavirus vaccination. Diagnosis of cervical intraepithelial neoplasia differed little between slides and corresponding digitized images.


Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge.
Functional magnetic resonance imaging (fMRI) of the human brain was used to study whether the amygdala is activated in response to emotional stimuli, even in the absence of explicit knowledge that such stimuli were presented. Pictures of human faces bearing fearful or happy expressions were presented to 10 normal, healthy subjects by using a backward masking procedure that resulted in 8 of 10 subjects reporting that they had not seen these facial expressions. The backward masking procedure consisted of 33 msec presentations of fearful or happy facial expressions, their offset coincident with the onset of 167 msec presentations of neutral facial expressions. Although subjects reported seeing only neutral faces, blood oxygen level-dependent (BOLD) fMRI signal in the amygdala was significantly higher during viewing of masked fearful faces than during the viewing of masked happy faces. This difference was composed of significant signal increases in the amygdala to masked fearful faces as well as significant signal decreases to masked happy faces, consistent with the notion that the level of amygdala activation is affected differentially by the emotional valence of external stimuli. In addition, these facial expressions activated the sublenticular substantia innominata (SI), where signal increases were observed to both fearful and happy faces--suggesting a spatial dissociation of territories that respond to emotional valence versus salience or arousal value. This study, using fMRI in conjunction with masked stimulus presentations, represents an initial step toward determining the role of the amygdala in nonconscious processing.


Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism.
A growing body of experimental and clinical literature indicates an association between Gaucher disease and parkinsonism, raising the possibility that convergent mechanisms may contribute to neurodegeneration in these disorders. The aim of this study was to determine whether there is a relationship between alpha-synuclein (alpha-syn), a key protein in Parkinson's disease pathogenesis, and abnormalities in glucocerebroside (GC) catabolism that lead to the development of Gaucher disease. We inhibited glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in neuroblastoma cells and mice to test whether a biological link exists between GCase activity and alpha-syn. After CBE exposure, enhanced alpha-syn protein was detected in differentiated cells challenged with CBE as compared to vehicle, with no change in alpha-syn mRNA. In the mouse model, after one injection of CBE, elevated nigral alpha-syn levels were also detected. Analyses by Western blot and confocal microscopy revealed that normal alpha-syn distribution was perturbed after CBE exposure with its accumulation apparent within nigral cell bodies as well as astroglia. These findings raise the possibility that alpha-syn may contribute to the cascade of events that promote neuronal dysfunction in Gaucher disease and are the first to implicate this protein as a plausible biological intersection between Gaucher disease and parkinsonism using a pharmacological model.


Immunomodulatory properties of Olea europaea leaf extract in intestinal inflammation.
Extracts from olive (Olea europaea) leaves are used in Mediterranean traditional medicine as anti-inflammatory agents. They contain antioxidant phenolic compounds, such as oleuropeoside, which could be interesting for the treatment of inflammatory conditions associated with oxidative stress in humans, including inflammatory bowel disease. The anti-inflammatory effects of olive leaf extract (0.5-25 mg/kg) were studied in two mice models of colitis (DSS and DNBS). Olive leaf extract (0.1-100 μg/mL) immunomodulatory effects were also investigated in different cell types and in ex vivo organ cultures of mucosal explants of healthy donors and Crohn's disease (CD) patients. The extract showed effect in both colitis models reducing the expression of proinflammatory mediators (IL-1β, TNF-α, and iNOS), and improving the intestinal epithelial barrier integrity restoring the expression of ZO-1, MUC-2, and TFF-3. These effects were confirmed in vitro. Furthermore, it reduced the production of proinflammatory mediators (IL-1β, IL-6, IL-8, and TNF-α) in intestinal mucosal samples from CD patients. Olive leaf extract presented intestinal anti-inflammatory activity in colitis mouse models, maybe be related to its immunomodulatory properties and the capacity to restore the intestinal epithelial barrier. Besides, the extract could also regulate the activity of cells involved in the inflammatory response.


Evidence of Autler-Townes splitting in high-order nonlinear processes.
We demonstrate Autler-Townes (AT) splitting of four-wave mixing in an electromagnetically induced transparency window, which results from the destructive interference between a three-photon process and a five-photon process. The primary and secondary AT splittings are achieved via induced atomic coherence in a four-level Y-type atomic system. Theoretical calculations fit well with the experimentally measured results. Such controlled multichannel splitting of nonlinear optical signals can have potential applications in optical communication and quantum information processing.


A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse.
The areca alkaloids comprise arecoline, arecaidine, guvacoline, and guvacine. Approximately 600 million users of areca nut products, for example, betel quid chewers, are exposed to these alkaloids, principally arecoline and arecaidine. Metabolism of arecoline (20 mg/kg p.o. and i.p.) and arecaidine (20 mg/kg p.o. and i.p.) was investigated in the mouse using a metabolomic approach employing ultra-performance liquid chromatography-time-of-flight mass spectrometric analysis of urines. Eleven metabolites of arecoline were identified, including arecaidine, arecoline N-oxide, arecaidine N-oxide, N-methylnipecotic acid, N-methylnipecotylglycine, arecaidinylglycine, arecaidinylglycerol, arecaidine mercapturic acid, arecoline mercapturic acid, and arecoline N-oxide mercapturic acid, together with nine unidentified metabolites. Arecaidine shared six of these metabolites with arecoline. Unchanged arecoline comprised 0.3-0.4%, arecaidine 7.1-13.1%, arecoline N-oxide 7.4-19.0%, and N-methylnipecotic acid 13.5-30.3% of the dose excreted in 0-12 h urine after arecoline administration. Unchanged arecaidine comprised 15.1-23.0%, and N-methylnipecotic acid 14.8%-37.7% of the dose excreted in 0-12 h urine after arecaidine administration. The major metabolite of both arecoline and arecaidine, N-methylnipecotic acid, is a novel metabolite arising from carbon-carbon double-bond reduction. Another unusual metabolite found was the monoacylglyceride of arecaidine. What role, if any, that is played by these uncommon metabolites in the toxicology of arecoline and arecaidine is not known. However, the enhanced understanding of the metabolic transformation of arecoline and arecaidine should contribute to further research into the clinical toxicology of the areca alkaloids.


National Trends in Outpatient Antihypertensive Prescribing in People with Dementia in the United States.
The objectives were to investigate national trends in outpatient antihypertensive prescribing in people with dementia in the United States between 2006 and 2012, and to investigate clinical and demographic factors associated with different antihypertensive prescribing patterns. This was an analysis of the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department component of the National Hospital Ambulatory Medical Care Survey (NHAMCS). Outpatient visits by people aged ≥65 years with documented dementia were analyzed. Complex samples multivariate logistic regression was conducted to estimate temporal trends and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for factors associated with prescribing of antihypertensives, multiple antihypertensives and different antihypertensive classes. There was a statistically significant increase in the proportion of physician visits by older people with dementia with a documented diagnosis of hypertension from 49.3% (95% CI: 41.3% -57.4%) in 2006 to 55.7% (95% CI: 50.2% -61.2%) in 2012. There were non-significant increases in overall antihypertensive use and the use of multiple antihypertensive classes. Male sex was associated with any antihypertensive use (AOR 1.37, 95% CI 1.02-1.84) and multiple antihypertensive class use (AOR 1.52, 95% CI 1.14-2.04). Black race (AOR 2.04, 95% CI 1.12-3.71) and Midwest residence (AOR 2.03, 95% CI 1.46-2.82) were associated with multiple antihypertensive use. There was an increase in documented hypertension in physician visits by older people with dementia from 2006 to 2012, but minimal increases in overall antihypertensive use. Various demographic and clinical factors were associated with the prescribing of antihypertensives in people with dementia.


MSY2 and MSY4 bind a conserved sequence in the 3' untranslated region of protamine 1 mRNA in vitro and in vivo.
Y-box proteins are major constituents of ribonucleoprotein particles (RNPs) which contain translationally silent mRNAs in gametic cells. We have recently shown that a sequence-specific RNA binding activity present in spermatogenic cells contains the two Y-box proteins MSY2 and MSY4. We show here that MSY2 and MSY4 bind a sequence, 5'-UCCAUCA-3', present in the 3' untranslated region of the translationally repressed protamine 1 (Prm1) mRNA. Using pre- and post-RNase T1-digested substrate RNAs, it was determined that MSY2 and MSY4 can bind an RNA of eight nucleotides containing the MSY2 and MSY4 binding site. Single nucleotide mutations in the sequence eliminated the binding of MSY2 and MSY4 in an electrophoretic mobility shift assay, and the resulting mutants failed to compete for binding in a competition assay. A consensus site of U(AC)C(A)CAU(C)CA(CU) (subscripts indicate nucleotides which do not disrupt YRS binding by MSY2 and MSY4), denoted the Y-box recognition site (YRS), was defined from this mutational analysis. These mutations in the YRS were further characterized in vivo using a novel application of the yeast three-hybrid system. Experiments with transgenic mice show that disruption of the YRS in vivo relieves Prm1-like repression of a reporter gene. The conservation of the RNA binding motifs among Y-box protein family members raises the possibility that other Y-box proteins may have previously unrecognized sequence-specific RNA binding activities.


[Cancer and the Kidney: A Deadly Embrace].
A deadly embrace occurs between cancer and chronic kidney disease. The estimation of kidney function in cancer patients is of utmost interest due to its direct impact on chemotherapy dosing, selection, and eligibility for chemotherapeutics. Overestimating kidney function (determined as estimated glomerular filtration rate -eGFR) can lead to overdosing and drug toxicity, while underestimating kidney function can prevent patients from receiving novel therapies. Notably, the current measures of eGFR are not validated in transplanted patients yet. The field of onconephrology ranges from nephrotoxicity of existing and novel therapeutics, paraproteinemias, and cancer-associated electrolyte imbalance, fluid and acid-base disturbances, the effects of the destruction of cancer cells, and acute and/or chronic kidney injuries. Recently, the therapeutic armamentarium has been enriched with new agents that interfere with specific proteins involved in oncogenesis. These are the so-called target therapies, which although acquired as "targeted" therapies do not have absolute specificity and selectivity and tend to inhibit multiple targets, often involving the kidney. Renal biopsy may be critical in managing these adverse effects. Moreover, primary hematological and oncological disorders can have significant kidney implications in the form of glomerular or nonglomerular diseases presenting with proteinuria, hematuria, hypertension, and kidney function decline, specifically including cast nephropathy or systemic light chain amyloidosis, and paraneoplastic glomerulopathies that occur as a result of occult malignancy, such as Membranous Nephropathy and Minimal Change disease.


Prostate cancer biomarkers: an update.
Many aspects of prostate cancer diagnosis and treatment could be greatly advanced with new, effective biomarkers. Prostate-specific antigen (PSA) has multiple weaknesses as a biomarker, such as not distinguishing well between cancer and benign prostatic hyperplasia or between indolent and aggressive cancers, thus leading to overtreatment, especially unnecessary biopsies. PSA also often fails to indicate accurately which patients are responding to a given treatment. Yet PSA is the only prostate cancer biomarker routinely used by urologists. Here, we provide updated information on the most relevant of the other biomarkers currently in use or in development for prostate cancer. Recent research shows improvement over using PSA alone by comparing total PSA (tPSA) or free PSA (fPSA) with new, related markers, such as prostate cancer antigen (PCA) 3, the individual molecular forms of PSA (proPSA, benign PSA, and intact PSA), and kallikreins other than PSA. Promising results have also been seen with the use of the fusion gene TMPRSS2:ERG and with various forms of the urokinase plasminogen activation receptor. Initially, there were high hopes for early PCA, but those data were not reproducible and thus research on early PCA has been abandoned. Much work remains to be done before any of these biomarkers are fully validated and accepted. Currently, the only markers discussed in this paper with Food and Drug Administration-approved tests are PCA 3 and an isoform of proPSA, [-2]proPSA. Assays are in development for most of the other biomarkers described in this paper. While the biomarker validation process can be long and filled with obstacles, the rewards will be great-in terms of both patient care and costs to the health care system.


Current Perspectives on Pathobiology of the Ductus Arteriosus.
The ductus arteriosus (DA) shunts blood away from the lungs during fetal life, but at birth this shunt is no longer needed and the vessel rapidly constricts. Postnatal persistence of the DA, patent ductus arteriosus (PDA), is predominantly a detrimental condition for preterm infants but is simultaneously a condition required to maintain systemic blood flow for infants born with certain severe congenital heart defects. Although PDA in preterm infants is associated with significant morbidities, there is controversy regarding whether PDA is truly causative. Despite advances in our understanding of the pathobiology of PDA, the optimal treatment strategy for PDA in preterm infants is unclear. Here we review recent studies that have continued to elucidate the fundamental mechanisms of DA development and pathogenesis.


Allograft versus autograft in posterior cruciate ligament reconstruction: an evidence-based systematic review.
Controversy exists as to the superior graft source for posterior cruciate ligament (PCL) reconstruction. Allogeneic and autogeneic tissue have unique advantages and disadvantages, but little is known about the performance of one versus the other. This study is an evidence-based, systematic literature review comparing clinical and functional outcomes of allograft and autograft PCL reconstruction. A search was conducted via the Cochrane and MEDLINE databases for all relevant studies meeting the following inclusion criteria: (1) English language, (2) human subjects, (3) between the years 1980 and 2011, (4) minimum 24-month follow-up, (5) measures of clinical and functional outcomes, and (6) patients with isolated grade II/III PCL injuries who had failed nonoperative management and were deemed clinically and functionally unstable. Excluded studies were (1) technique articles, (2) case reports, and (3) patients with additional ligamentous or bony injuries. A total of 19 relevant studies were identified (2 direct comparison, 5 allograft, and 12 autograft). No appreciable differences between allograft and autograft PCL reconstruction were identified. A paucity of data exists comparing allogeneic and autogeneic PCL reconstruction, but satisfactory clinical and functional results have been obtained with both graft sources.


Millimeter-wave achromatic half-wave plate.
We have constructed an achromatic half-wave plate (AHWP) suitable for the millimeter wavelength band. The AHWP was made from a stack of three sapphire a-cut birefringent plates with the opticalaxes of the middle plate rotated by 50.5 deg with respect to the aligned axes of the other plates. The measured modulation efficiency of the AHWP at 110 GHz was 96 +/- 1.5%. In contrast, the modulation efficiency of a single sapphire plate of the same thickness was 43 +/- 4%. Both results are in close agreement with theoretical predictions. The modulation efficiency of the AHWP was constant as a function of incidence angles between 0 and 15 deg. We discuss design parameters of an AHWP in the context of astrophysical broadband polarimetry at the millimeter wavelength band.


A mechanistic study of silica-etching by hot water.
The etching of colloidal silica by hot water provides a green chemistry method for the preparation of mesoporous silica. Nevertheless, the reaction mechanism of this etching process has not been elucidated and its reproducibility is often questionable, which has hindered its widespread application in the preparation of mesoporous silica materials. Herein, we present a systematic study on the hot-water etching of sol-gel derived silica shells coated on α-Fe2O3 particles. Transmission electron microscopy and infrared spectroscopy studies provide substantial evidence that colloidal silica with low hydrolysis and condensation degrees (or aging degrees) is preferentially etched by hot water. More importantly, we show that the aging degree of silica shells, which determines the etching rate, can be precisely tuned by controlling the sol-gel preparation time and the storage time in room-temperature water prior to hot-water etching. These results provide novel insights into the physicochemical properties of sol-gel derived colloidal silica and the mechanistic understanding of the reaction kinetics of silica etching by hot water.


[Mitochondrial DNA polymorphism in Russian population form five oblasts of the European part of Russia].
New data on mitochondrial DNA polymorphism among Russian population from five oblasts, located within the main ethnic area of Russians, specifically, Ryazan' oblast, Ivanovo oblast, Vologda oblast, Orel oblast, and Tambov oblast (N = 177) are presented. RFLP analysis of the mtDNA coding region showed that most of the mtDNA diversity in the populations examined could be described by main European haplogroups H, U, T, J, K, I, V, W, and X. Haplogroup frequency distribution patterns in the populations of interest were analyzed in comparison with the European and Uralic populations. Based on the haplogroup frequencies, the indices of intraethnic population diversity, Wright's F(st) statistics, and the values of squared deviation from the mean, as well as genetic distances between Russians and European and Uralic populations were estimated. Analysis of these indices along with the anthropological data provided identification of a number of regional groups within the populations examined, which could either result from the interaction of ancient Slavs with different non-Slavic tribes, or could be caused by the ethnic heterogeneity of the ancient Slavs themselves.


Quantitative analysis of replication-related mutation and selection pressures in bacterial chromosomes and plasmids using generalised GC skew index.
Due to their bi-directional replication machinery starting from a single finite origin, bacterial genomes show characteristic nucleotide compositional bias between the two replichores, which can be visualised through GC skew or (C-G)/(C+G). Although this polarisation is used for computational prediction of replication origins in many bacterial genomes, the degree of GC skew visibility varies widely among different species, necessitating a quantitative measurement of GC skew strength in order to provide confidence measures for GC skew-based predictions of replication origins. Here we discuss a quantitative index for the measurement of GC skew strength, named the generalised GC skew index (gGCSI), which is applicable to genomes of any length, including bacterial chromosomes and plasmids. We demonstrate that gGCSI is independent of the window size and can thus be used to compare genomes with different sizes, such as bacterial chromosomes and plasmids. It can suggest the existence of different replication mechanisms in archaea and of rolling-circle replication in plasmids. Correlation of gGCSI values between plasmids and their corresponding host chromosomes suggests that within the same strain, these replicons have reproduced using the same replication machinery and thus exhibit similar strengths of replication strand skew. gGCSI can be applied to genomes of any length and thus allows comparative study of replication-related mutation and selection pressures in genomes of different lengths such as bacterial chromosomes and plasmids. Using gGCSI, we showed that replication-related mutation or selection pressure is similar for replicons with similar machinery.


The structure of a lanthanide complex at an extractant/water interface studied using heterodyne-detected vibrational sum frequency generation.
Solvent extraction plays an integral part in the separation and purification of metals. Because extractants generally used as complexing agents for metal extractions, such as di-(2-ethylhexyl)phosphoric acid (HDEHP) for lanthanide extractions, are amphiphilic, they come to an organic/water interface, and the interface plays a crucial role as the site of the formation of metal complexes and the subsequent transfer reaction to an organic phase. Despite the importance of the interface for metal solvent extractions, its molecular-level structure is unclear because of the experimental difficulties. Here we studied the structure of a trivalent europium (Eu3+) complex with HDEHP formed at the HDEHP monolayer/water interface using heterodyne-detected vibrational sum frequency generation (HD-VSFG) spectroscopy. The study on the HDEHP/water interface enables us to investigate the structure of the interfacial Eu3+ complex by excluding the migration of Eu3+ into an organic phase after the complex formation at the interface. The interface-selective vibrational Imχ(2) spectra observed using HD-VSFG of the interface of HDEHP/aqueous Eu(NO3)3 solution in the 2800-3500 cm-1 region indicate that Eu3+ at the HDEHP/water interface is bonded by HDEHP from the air side and by water molecules from the water side. To the best of our knowledge, such metal complex structures have not been identified in organic or water solutions.


An Axiology of Information Security for Futuristic Neuroprostheses: Upholding Human Values in the Context of Technological Posthumanization.
Previous works exploring the challenges of ensuring information security for neuroprosthetic devices and their users have typically built on the traditional InfoSec concept of the "CIA Triad" of confidentiality, integrity, and availability. However, we argue that the CIA Triad provides an increasingly inadequate foundation for envisioning information security for neuroprostheses, insofar as it presumes that (1) any computational systems to be secured are merely instruments for expressing their human users' agency, and (2) computing devices are conceptually and practically separable from their users. Drawing on contemporary philosophy of technology and philosophical and critical posthumanist analysis, we contend that futuristic neuroprostheses could conceivably violate these basic InfoSec presumptions, insofar as (1) they may alter or supplant their users' biological agency rather than simply supporting it, and (2) they may structurally and functionally fuse with their users to create qualitatively novel "posthumanized" human-machine systems that cannot be secured as though they were conventional computing devices. Simultaneously, it is noted that many of the goals that have been proposed for future neuroprostheses by InfoSec researchers (e.g., relating to aesthetics, human dignity, authenticity, free will, and cultural sensitivity) fall outside the scope of InfoSec as it has historically been understood and touch on a wide range of ethical, aesthetic, physical, metaphysical, psychological, economic, and social values. We suggest that the field of axiology can provide useful frameworks for more effectively identifying, analyzing, and prioritizing such diverse types of values and goods that can (and should) be pursued through InfoSec practices for futuristic neuroprostheses.


Aberrant functional connectivity within the basal ganglia of patients with Parkinson's disease.
Resting state functional MRI (rs-fMRI) has been previously shown to be a promising tool for the assessment of early Parkinson's disease (PD). In order to assess whether changes within the basal ganglia network (BGN) are disease specific or relate to neurodegeneration generally, BGN connectivity was assessed in 32 patients with early PD, 19 healthy controls and 31 patients with Alzheimer's disease (AD). Voxel-wise comparisons demonstrated decreased connectivity within the basal ganglia of patients with PD, when compared to patients with AD and healthy controls. No significant changes within the BGN were seen in AD, when compared to healthy controls. Moreover, measures of functional connectivity extracted from regions within the basal ganglia were significantly lower in the PD group. Consistent with previous radiotracer studies, the greatest change when compared to the healthy control group was seen in the posterior putamen of PD subjects. When combined into a single component score, this method differentiated PD from AD and healthy control subjects, with a diagnostic accuracy of 81%. Rs-fMRI can be used to demonstrate the aberrant functional connectivity within the basal ganglia of patients with early PD. These changes are likely to be representative of patho-physiological basal ganglia dysfunction and are not associated with generalised neurodegeneration seen in AD. Further studies are necessary to ascertain whether this method is sensitive enough to detect basal ganglia dysfunction in prodromal PD, and its utility as a potential diagnostic biomarker for premotor and early motoric disease.


Economic implications of manganese neurotoxicity.
Manganese neurotoxicity is linked primarily to inhalation exposure, and its clinical features are almost totally based on high doses, such as those experienced by miners. Manifestations of lower level exposures can take two forms. One is the appearance of neurobehavioral deficits. A second, equally subtle, form is as a promoter, borrowing the term used in carcinogenesis, of neurodegenerative disease. Such low-level environmental exposures may be more potent than expected if they occur as ultrafine particles able to penetrate directly into the brain. The neurological disorder linked most closely to manganese is Parkinson's disease (PD). Although most observers recognize that the features of manganese-induced parkinsonism differ from those of idiopathic PD, they overlap considerably. The overlaps should be expected because the underlying lesions, although distinguishable, are closely linked because they belong to structures with complex interdependent circuitry. Such interdependence makes it feasible to undertake an analysis of how manganese neurotoxicity might elevate the risks of PD. A relatively small increment in risk, expressed as a leftward shift in the age prevalence of PD, incurs significant economic costs.


Direct inhibition of the ubiquitin-proteasome pathway by ester bond-containing green tea polyphenols is associated with increased expression of sterol regulatory element-binding protein 2 and LDL receptor.
Green tea has been shown to lower plasma cholesterol, associated with up-regulation of the low-density lipoprotein receptor (LDLR) although the responsible molecular mechanism is unknown. Previously, we reported that ester bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG], potently inhibit the tumor cellular proteasome activity, which may contribute to the cancer-preventative effect of green tea. In the current study, we hypothesize that the proteasome is a heart disease-associated molecular target of GTPs. We have shown that ester bond-containing GTPs, including (-)-EGCG, potently inhibit the proteasomal activity in intact hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cells, as evident by accumulation of ubiquitinated proteins and three natural proteasome targets (p27, IkappaB-alpha and Bax). (-)-EGCG selectively inhibits the chymotrypsin-like, but not trypsin-like, activity of the proteasome. Associated with proteasome inhibition by ester bond-containing GTPs, there was a significant, time- and concentration-dependent increase in levels of the cleaved, activated, but not the precursor, form of sterol regulatory element-binding protein 2 (SREBP-2), an essential factor for LDLR transcription. Subsequently, LDL receptor expression was increased dramatically in HepG2 and HeLa cells treated with (-)-EGCG. Our results suggest that ester bond-containing GTPs inhibit ubiquitin/proteasome-mediated degradation of the active SREBP-2, resulting in up-regulation of LDLR. This identified molecular mechanism may be related to the previously reported cholesterol-lowering and heart disease-preventative effects of green tea.


Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosol.
Electronic cigarettes (EC) deliver aerosol by heating fluid containing nicotine. Cartomizer EC combine the fluid chamber and heating element in a single unit. Because EC do not burn tobacco, they may be safer than conventional cigarettes. Their use is rapidly increasing worldwide with little prior testing of their aerosol. We tested the hypothesis that EC aerosol contains metals derived from various components in EC. Cartomizer contents and aerosols were analyzed using light and electron microscopy, cytotoxicity testing, x-ray microanalysis, particle counting, and inductively coupled plasma optical emission spectrometry. The filament, a nickel-chromium wire, was coupled to a thicker copper wire coated with silver. The silver coating was sometimes missing. Four tin solder joints attached the wires to each other and coupled the copper/silver wire to the air tube and mouthpiece. All cartomizers had evidence of use before packaging (burn spots on the fibers and electrophoretic movement of fluid in the fibers). Fibers in two cartomizers had green deposits that contained copper. Centrifugation of the fibers produced large pellets containing tin. Tin particles and tin whiskers were identified in cartridge fluid and outer fibers. Cartomizer fluid with tin particles was cytotoxic in assays using human pulmonary fibroblasts. The aerosol contained particles >1 µm comprised of tin, silver, iron, nickel, aluminum, and silicate and nanoparticles (<100 nm) of tin, chromium and nickel. The concentrations of nine of eleven elements in EC aerosol were higher than or equal to the corresponding concentrations in conventional cigarette smoke. Many of the elements identified in EC aerosol are known to cause respiratory distress and disease. The presence of metal and silicate particles in cartomizer aerosol demonstrates the need for improved quality control in EC design and manufacture and studies on how EC aerosol impacts the health of users and bystanders.


ESPGHAN Committee on Nutrition Position Paper. Intravenous Lipid Emulsions and Risk of Hepatotoxicity in Infants and Children: a Systematic Review and Meta-analysis.
The aim of the present article was to perform a systematic review with meta-analysis of available scientific evidence regarding the role of different intravenous lipid emulsions (ILE) in the pathogenesis of cholestasis and parenteral nutrition-associated liver disease. A systematic review of the literature (up to March 2015) identified 23 randomized controlled trials (RCTs). Of these, 17 were performed in preterm infants or critically ill neonates with a short duration of intervention, 2 in older children with short-term use (following surgery or bone marrow transplantation), 1 in neonates with long-term use, and 3 in infants and children receiving long-term parenteral nutrition (PN). Meta-analysis showed no differences in the rate of cholestasis or bilirubin levels associated with short-term use of different ILEs. Because of high heterogeneity of the long-term studies no meta-analysis could be performed. Available studies found that the use of multicomponent fish oil (FO)-containing ILE compared with pure soya bean oil (SO), ILE-reduced liver enzymes, and bilirubin levels in noncholestatic children on long-term PN and one other RCT found that FO-based ILE-reversed cholestasis in a proportion of patients. The ESPGHAN Committee on Nutrition concludes that there is no evidence of a difference in rates of cholestasis or bilirubin levels between different ILE for short-term use in neonates. The use of multicomponent FO-containing ILE may contribute to a decrease in total bilirubin levels in children with IF on prolonged PN. Well-designed RCTs are, however, lacking and long-term effects have not been determined.


Projected coupled cluster theory.
Coupled cluster theory is the method of choice for weakly correlated systems. But in the strongly correlated regime, it faces a symmetry dilemma, where it either completely fails to describe the system or has to artificially break certain symmetries. On the other hand, projected Hartree-Fock theory captures the essential physics of many kinds of strong correlations via symmetry breaking and restoration. In this work, we combine and try to retain the merits of these two methods by applying symmetry projection to broken symmetry coupled cluster wave functions. The non-orthogonal nature of states resulting from the application of symmetry projection operators furnishes particle-hole excitations to all orders, thus creating an obstacle for the exact evaluation of overlaps. Here we provide a solution via a disentanglement framework theory that can be approximated rigorously and systematically. Results of projected coupled cluster theory are presented for molecules and the Hubbard model, showing that spin projection significantly improves unrestricted coupled cluster theory while restoring good quantum numbers. The energy of projected coupled cluster theory reduces to the unprojected one in the thermodynamic limit, albeit at a much slower rate than projected Hartree-Fock.


Technique for measurement of the Raman gain coefficient in optical fibers.
We demonstrate a simple, novel technique for measurement of the Raman gain spectrum in optical fibers. We measure the stimulated Raman scattered power generated by a square pulse as a function of its pulse width. Because of fiber dispersion, increasing the pulse width increases the interaction length of the pump and Stokes pulses and leads to a higher Stokes power. The dependence of growth rate of Stokes power on pulse width gives the Raman gain coefficient. Our technique does not require calibration against a standard or absolute measurement of the Stokes signal. We show that gain values obtained with this technique agree well with direct pump-probe measurements.


Abnormal osmotic regulation in trpv4-/- mice.
Osmotic homeostasis is one of the most aggressively defended physiological parameters in vertebrates. However, the molecular mechanisms underlying osmotic regulation are poorly understood. The transient receptor potential channel, vanilloid subfamily (TRPV4), is an osmotically activated ion channel that is expressed in circumventricular organs in the mammalian CNS, which is an important site of osmotic sensing. We have generated trpv4-null mice and observed abnormalities of their osmotic regulation. trpv4-/- mice drank less water and became more hyperosmolar than did wild-type littermates, a finding that was seen with and without administration of hypertonic saline. In addition, plasma levels of antidiuretic hormone were significantly lower in trpv4-/- mice than in wild-type littermates after a hyperosmotic challenge. Continuous s.c. infusion of the antidiuretic hormone analogue, dDAVP, resulted in systemic hypotonicity in trpv4-/- mice, despite the fact that their renal water reabsorption capacity was normal. Thus, the response to both hyper- and hypoosmolar stimuli is impaired in trpv4-/- mice. After a hyperosmolar challenge, there was markedly reduced expression of c-FOS in the circumventricular organ, the organum vasculosum of the lamina terminalis, of trpv4-/- mice compared with wild-type mice. This finding suggests that there is an impairment of osmotic sensing in the CNS of trpv4-/- mice. These data indicate that TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS.


Localization of the developmental timing regulator Lin28 to mRNP complexes, P-bodies and stress granules.
Lin28 is a conserved cytoplasmic protein with an unusual pairing of RNA-binding motifs: a cold shock domain and a pair of retroviral-type CCHC zinc fingers. In the nematode C. elegans, it is a regulator of developmental timing. In mammals, it is abundant in diverse types of undifferentiated cells. However, its molecular function is unknown. In pluripotent mammalian cells, Lin28 is observed in RNase-sensitive complexes with poly(A)-binding protein, and in polysomal fractions of sucrose gradients, suggesting it is associated with translating mRNAs. Upon cellular stress, Lin28 locates to stress granules, which contain non-translating mRNA complexes. However, Lin28 also localizes to cytoplasmic processing bodies, or P-bodies, sites of mRNA degradation and microRNA regulation, consistent with it acting to regulate mRNA translation or stability. Mutational analysis shows that Lin28's conserved RNA binding domains cooperate to put Lin28 in mRNPs, but that only the CCHC domain is required for localization to P-bodies. When both RNA-binding domains are mutated, Lin28 accumulates in the nucleus, suggesting that it normally shuttles from nucleus to cytoplasm bound to RNA. These studies are consistent with a model in which Lin28 binds mRNAs in the nucleus and accompanies them to ribosomes and P-bodies. We propose that Lin28 influences the translation or stability of specific mRNAs during differentiation.


The economic value of ecosystem services in the Great Barrier Reef: our state of knowledge.
This article reviews literature relating to the Great Barrier Reef (GBR) and aims to assess the current state of knowledge about (1) the "value" of ecosystem services (ES) provided by the GBR and (2) the way in which activities that are carried out in regions adjacent to the GBR affect those values. It finds that most GBR valuation studies have concentrated on a narrow range of ES (e.g., tourism and fishing) and that little is known about other ES or about the social, temporal, and spatial distribution of those services. Just as the reef provides ES to humans and to other ecosystems, so too does the reef receive a variety of ES from adjoining systems (e.g., mangroves). Yet, despite the evidence that the reef's ability to provide ES has been eroded because of recent changes to adjoining ecosystems, little is known about the value of the ES provided by adjoining systems or about the value of recent changes. These information gaps may lead to suboptimal allocations of resource use within multiple realms.


An in vitro co-culture model of esophageal cells identifies ascorbic acid as a modulator of cell competition.
The evolutionary dynamics between interacting heterogeneous cell types are fundamental properties of neoplastic progression but can be difficult to measure and quantify. Cancers are heterogeneous mixtures of mutant clones but the direct effect of interactions between these clones is rarely documented. The implicit goal of most preventive interventions is to bias competition in favor of normal cells over neoplastic cells. However, this is rarely explicitly tested. Here we have developed a cell culture competition model to allow for direct observation of the effect of chemopreventive or therapeutic agents on two interacting cell types. We have examined competition between normal and Barrett's esophagus cell lines, in the hopes of identifying a system that could screen for potential chemopreventive agents. One fluorescently-labeled normal squamous esophageal cell line (EPC2-hTERT) was grown in competition with one of four Barrett's esophagus cell lines (CP-A, CP-B, CP-C, CP-D) under varying conditions and the outcome of competition measured over 14 days by flow cytometry. We demonstrate that ascorbic acid (vitamin C) can help squamous cells outcompete Barrett's cells in this system. We are also able to show that ascorbic acid's boost to the relative fitness of squamous cells was increased in most cases by mimicking the pH conditions of gastrointestinal reflux in the lower esophagus. This model is able to integrate differential fitness effects on various cell types, allowing us to simultaneously capture effects on interacting cell types without having to perform separate experiments. This model system may be used to screen for new classes of cancer prevention agents designed to modulate the competition between normal and neoplastic cells.