bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular insights into the WW domain of the Golabi‐Ito‐Hall syndrome protein PQBP1
Authors: Sudol Marius , McDonald Caleb B. , Farooq Amjad
Published: March 2012

The WW domain‐containing PQBP1 (polyglutamine tract‐binding protein 1) protein regulates mRNA processing and gene transcription. Mutations in the PQBP1 gene were reported in several X chromosome‐linked intellectual disability (XLID) disorders, including Golabi‐Ito‐Hall (GIH) syndrome. The missense mutation in the GIH syndrome maps within a functional region of the PQBP1 protein known as the WW domain. The causative mutation of PQBP1 replaces the conserved tyrosine (Y) at position 65 within the aromatic core of the WW domain to cysteine (C), which is a chemically significant change. In this short review, we analyze structural models of the Y65C mutated and wild type WW domains of PQBP1 in order to infer potential molecular mechanisms that render the mutated PQBP1 protein inactive in terms of ligand binding and its function as a regulator of mRNA splicing.
Molecular dynamics simulation of GTPase activity in polymers of the cell division protein FtsZ
Authors: Martín-García Fernando , Salvarelli Estefanía , Mendieta-Moreno Jesús Ignacio , Vicente Miguel , Mingorance Jesús , Mendieta Jesús , Gómez-Puertas Paulino
Published: March 2012

FtsZ, the prokaryotic ortholog of tubulin, assembles into polymers in the bacterial division ring. The interfaces between monomers contain a GTP molecule, but the relationship between polymerization and GTPase activity is not unequivocally proven. A set of short FtsZ polymers were modelled and the formation of active GTPase structures was monitored using molecular dynamics. Only the interfaces nearest the polymer ends exhibited an adequate geometry for GTP hydrolysis. Simulated conversion of interfaces from close‐to‐end to internal position and vice versa resulted in their spontaneous rearrangement between active and inactive conformations. This predicted behavior of FtsZ polymer ends was supported by in vitro experiments.
Effects of parity and mode of delivery on urinary incontinence among postmenopausal women in Taiwan
Authors: Hsieh Ching‐Hung , Chang Wei‐Chun , Su Tsung‐Hsien , Lin Tzu‐Yin , Lee Meng‐Chin , Chang Shao‐Tung
Published: March 2012

Objective

To investigate the association between the prevalence of urinary incontinence and parity or mode of delivery among Taiwanese women aged 60 years or older.

Methods

Between July 1999 and December 2000, a nationwide epidemiologic study was conducted in Taiwan among 2410 women selected by a multistage random sampling method. Face‐to‐face interviews with 1517 women were conducted. The relationship between the prevalence of urinary incontinence and the number of vaginal deliveries or number of cesarean deliveries was assessed by frequency and Pearson χ2 test using a significance level of less than 0.05. Logistic regression was used to investigate the significance of dichotomous dependent variables.

Results

Decades ago, most Taiwanese women (1435 of 1511 respondents, 94.97%,) gave birth via vaginal delivery and the rate of cesarean delivery was low (20 of 1513 respondents, 1.32%). Parity (odds ratio [OR], 2.42; 95% confidence interval [CI], 0.87–6.71; P = 0.091), vaginal delivery (OR, 0.76; 95% CI, 0.39–1.47; P = 0.408), and cesarean delivery (OR, 1.47; 95% CI, 0.59–3.70; P = 0.409) did not increase the risk of urinary incontinence.

Conclusion

There was no association between urinary incontinence and parity or mode of delivery among Taiwanese postmenopausal women decades after their first delivery.
Cannabinoid receptor 1 (CB1R) expression in rat dental pulp
Authors: Mitrirattanakula Somsak , Poomsawat Sopee , Fuangtharnthip Pornpoj
Published: March 2012

Purpose of the research: Accumulating evidence supports the role of the cannabinoid system in providing an antinociceptive effect in various painful conditions. This effect is mediated through the Cannabinoid receptor 1 (CB1R) expressed on nociceptive afferent nerve terminals. To investigate whether this receptor plays a similar role in dental pain, we studied the presence and distribution of CB1R in rat dental pulp. Pulps from 28 maxillary molars were immunohistochemically stained with an antibody against CB1R.

Principal results: Of all tooth specimens, CB1R immunoreactivity (CB1R‐ir) was observed to be associated with nerve fibers in radicular pulp and was seen as a continuous network in the subodontoblastic layer.

Major conclusion: CB1R was present on nerve fibers in rat dental pulp and possibly plays a role in dental pain mechanisms.
Reversal of severe methotrexate-induced intestinal damage using enteral n-3 fatty acids
Authors: Koppelmann Tal , Pollak Yulia , Mogilner Jorge , Bejar Jacob , Coran Arnold G. , Sukhotnik Igor
Published: March 2012

Growing evidence suggests that n-3 PUFA and their specific lipid mediators can reduce the activity of inflammatory processes. In the present study, we evaluated the effects of oral n-3 PUFA supplementation on intestinal structural changes, enterocyte proliferation and apoptosis during methotrexate (MTX)-induced intestinal damage in the rat. A total of thirty-two male rats were divided into four experimental groups: control (CONTR) rats; CONTR-n-3 PUFA rats treated with oral administration of n-3 PUFA at a dose of 300 μg/kg once per d 72 h before and 72 h following vehicle injection; MTX rats treated with a single dose of MTX; MTX-n-3 PUFA rats treated with oral n-3 PUFA following the injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis determined 72 h following MTX injection. Real-time PCR was used to determine B-cell lymphoma 2 (Bcl2)-associated X protein (Bax) and Bcl2 mRNA expression. Western blotting was used to determine phosphorylated extracellular signal-related kinase, β-catenin, Bax and Bcl2 protein levels. MTX-n-3 PUFA rats demonstrated a greater jejunal and ileal bowel weight, greater ileal mucosal weight, greater ileal mucosal DNA and protein levels, greater villus height in the jejunum and ileum and crypt depth in the ileum, compared with MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-n-3 PUFA rats (v. MTX) was accompanied by decreased Bax mRNA and protein expression and increased Bcl2 mRNA levels. Thus, the treatment with oral n-3 PUFA prevented mucosal injury and improved intestinal recovery following MTX-injury in rats.
The effect of raw vegetable and fruit intake on thyroid cancer risk among women: a case–control study in South Korea
Authors: Jung Su Kyoung , Kim Kirang , Tae Kyung , Kong Gu , Kim Mi Kyung
Published: March 2012

Thyroid cancer is the most common cancer among Korean women. However, there are few data on dietary factors related to thyroid cancer risk. The objective of the present study was to evaluate the association between raw vegetables and fruits intake and thyroid cancer in a case–control study. We included 111 histologically confirmed malignant thyroid cancer cases and 115 benign cases. Controls who did not have nodules in thyroid ultrasonography were matched to cases by age ( ± 2 years). Food and nutrient intakes were estimated using a quantitative FFQ with 121 items. Conditional logistic regression analysis was used to obtain OR and corresponding 95 % CI. The intake of total vegetables was not associated with malignant thyroid cancer, but inversely associated with benign cases. High raw vegetable intake was inversely associated with thyroid cancer risk both in malignant and benign cases (Pfor trend = 0·01 in both malignant and benign cases). Among fruits, persimmon intake had an inverse association with thyroid cancer risk in both malignant and benign cases (Pfor trend = 0·06 in malignant cases;Pfor trend = 0·01 in benign cases) and tangerine intake had an inverse association in malignant cases (Pfor trend = 0·03). The frequency of consumption of raw vegetables and persimmon also had a consistent inverse association in both malignant and benign cases. These results suggest that high consumption of raw vegetables, persimmons and tangerines may decrease thyroid cancer risk and help prevent early-stage thyroid cancer.
A View from Afar: How Colombia Sees China
Authors: Armony Ariel C.
Published: March 2012

The fast-paced landing of China in Latin America raises the question of how such a complex relationship is being built from little previous contact. Focusing on Colombia's printed media, the article examines the construction of China's public image. A Janus-faced view of China is initially revealed: a growing power perceived as an auspicious trade partner on the one hand; a troubling new actor in the international context on the other. Further analysis shows shades of grey that reveal a multifaceted, continuously evolving image of China that tells us much about both countries. The depiction of China's rising power, whose direction and purpose suggest a paradigm of “modernity without enlightment,” brings light to Colombia's unsettled accounts with democracy and development. The article sets a launching pad for further research on such mutually constitutive relationships.
The “Socialist Other”: Cuba in Chinese Ideological Debates since the 1990s
Authors: Cheng Yinghong
Published: March 2012

This article offers an analytical introduction to some important Cuba-related discussions in China in the last two-and-a-half decades. No Latin American nation has been treated like Castros' (Fidel and Raul) Cuba in China's ideological development. Cuba's revolutionary experience in the past and the regime's defiance of major global trends – from retreat of socialism to advancement of neo-liberalism – correspond to a wide range of opinions in China and are exploited by them to address their own concerns. To borrow Orientalist analysis, just like the “Other” helps define “Self,” as a “socialist Other,” Cuba in Chinese perception often reflects China's own confusions and contradictions.
Usual folic acid intakes: a modelling exercise assessing changes in the amount of folic acid in foods and supplements, National Health and Nutrition Examination Survey, 2003–2008
Authors: Tinker Sarah C , Cogswell Mary E , Hamner Heather C , Berry Robert J
Published: March 2012

Objective

The USA currently fortifies enriched cereal grain products (ECGP) with folic acid at 140 μg/100 g. In addition, folic acid can be voluntarily added to ready-to-eat cereals (RTEC) up to 400 μg/serving and it is found in many dietary supplements, most often at a dose of 400 μg. We sought to model folic acid intake under various fortification and supplementation scenarios.

Design

The National Health and Nutrition Examination Survey is a population-based cross-sectional survey representative of the non-institutionalized, civilian US population. Information on folic acid intake is collected in two 24 h dietary recalls and survey questions on dietary supplement use, which allows estimation of usual total folic acid intake. We modelled five different levels of folic acid fortification in ECGP, while varying the amounts in RTEC and dietary supplements.

Setting

United States.

Subjects

US adults (n 14 353) aged ≥19 years; non-pregnant women of childbearing age (n 4272).

Results

The percentage of adults with usual daily folic acid intake above the tolerable upper intake level of 1000 μg was influenced more by the typical amount in supplements, while the median intake was influenced more by the ECGP fortification level. By manipulating the amount in at least two sources, it was possible to shift the distribution such that more women of childbearing age consumed the recommended intake of 400 μg of folic acid without increasing the percentage of adults with intake above the tolerable upper intake level. The results varied among population subgroups.

Conclusions

Our results suggest that combined strategies are required to meet population recommendations for folic acid intake.
Diagnostik der Blut-Verletzungs-Spritzen-Angst
Authors: Voßbeck-Elsebusch Anna N. , Schroers Lioba K. , Gerlach Alexander L.
Published: March 2012

Zusammenfassung. Theoretischer Hintergrund: Zur Erfassung von Blut-Verletzungs-Spritzen-Ängsten sollte für den deutschen Sprachraum ein valider Fragebogen mit klarer Faktorenstruktur entwickelt werden. Fragestellung: Entwicklung eines neuen Messinstrumentes, welches auf die Erhebung von Blut-Verletzungs-Spritzen-Ängstlichkeit fokussiert. Methode: Entwicklung und Validierung eines Fragebogens an 340 Studenten, 20 Phobikern, 20 Kontrollpersonen und 18 Blutspendern. Ergebnisse: Es ergab sich ein Fragebogen mit 20 Items. Die Retest-Korrelation war hoch (rtt(42) = .78). Die Validitätsanalyse ergab hohe Korrelationen mit konstruktnahen Fragebögen, niedrige Korrelationen mit konstruktfernen Fragebögen und eine gute Differenzierung zwischen Phobikern und Kontrollpersonen. Ab einem Cut-Off von 44 (Range 20 bis 140) sollte das Vorliegen einer Blut-Verletzungs-Spritzen-Phobie geprüft werden. Schlussfolgerungen: Es konnte ein reliabler und valider deutscher Fragebogen mit vier klar definierten Faktoren entwickelt werden.
Lunar precursor effects in the solar wind and terrestrial magnetosphere
Authors: Halekas J. S. , Poppe A. R. , Farrell W. M. , Delory G. T. , Angelopoulos V. , McFadden J. P. , Bonnell J. W. , Glassmeier K. H. , Plaschke F. , Roux A. , Ergun R. E.
Published: March 2012

The two ARTEMIS probes observe significant precursor activity upstream from the Moon, when magnetically connected to the dayside lunar surface. The most common signature consists of high levels of whistler wave activity near half of the electron cyclotron frequency. This precursor activity extends to distances of many thousands of km, in both the solar wind and terrestrial magnetosphere. In the magnetosphere, electrons reflect from a combination of magnetic and electrostatic fields above the lunar surface, forming loss cone distributions. In the solar wind they generally form conics, as a result of reflection from an obstacle moving with respect to the plasma frame (just as at a shock). The anisotropy associated with these reflected electrons provides the free energy source for the whistlers, with cyclotron resonance conditions met between the reflected source population and Moonward‐propagating waves. These waves can in turn affect incoming plasma, and we observe significant perpendicular electron heating and plasma density depletions in some cases. In the magnetosphere, we also observe broadband electrostatic modes driven by beams of secondary electrons and/or photoelectrons accelerated outward from the surface. We also occasionally see waves near the ion cyclotron frequency in the magnetosphere. These lower frequency waves, which may result from the presence of ions of lunar origin, modulate the whistlers described above, as well as the electrons. Taken together, our observations suggest that the presence of the Moon leads to the formation of an upstream region analogous in many ways to the terrestrial electron foreshock.
Continental constriction and oceanic ice‐cover thickness in a Snowball‐Earth scenario
Authors: Tziperman Eli , Abbot Dorian S. , Ashkenazy Yosef , Gildor Hezi , Pollard David , Schoof Christian G. , Schrag Daniel P.
Published: March 2012

Ice flow over a Snowball ocean was shown in recent years to be capable of very effectively homogenizing ice thickness globally. Previous studies all used local or one‐dimensional global (latitude‐only) models, formulated in a way that is difficult to extend to two‐dimensional global configuration. This paper uses a two‐dimensional global ice flow model to study the effects of continental constriction on ice flow and ice thickness in a Snowball‐Earth scenario using reconstructed Neoproterozoic landmass configuration. Numerical simulations and scaling arguments are used to show that various configurations of continents and marginal seas which are not represented by one dimensional models lead to large ice thickness variations, including narrow areas between sub‐continents and marginal seas whose entrance is constricted. This study ignores many known important factors such as thermodynamic, optical effects, dust and dust transport, and is therefore meant as a process study focusing on one specific effect, rather than a realistic simulation of Neoproterozoic ice thickness. The model formulation developed here generalizes and extends previous results in several ways, including the introduction of corrections due to spherical coordinates and lateral geometry. This study is therefore a step toward coupling Snowball ice flow models to general circulation ocean and atmospheric models and allowing a more quantitative simulation of Neoproterozoic Snowball ice thickness.
Numerical study on the impact of the 18.6‐year period nodal tidal cycle on water masses in the subarctic North Pacific
Authors: Osafune S. , Yasuda I.
Published: March 2012

A series of numerical experiments is performed to test the hypothesis that temporal variations in localized strong tidal mixing related to the 18.6‐year period nodal tidal cycle induce water mass variations. It is suggested that enhanced mixing around the Bering Sea, as that around the Okhotsk Sea, have an impact on water masses broadly in the North Pacific including the Bering Sea and the Okhotsk Sea. Oscillatory tidal mixing with a 18.6‐year period reproduces water mass variations in salinity and isopycnal potential temperature around the subarctic North Pacific that are qualitatively consistent with observed variations. When the amplitude of oscillatory vertical diffusivity is 15% of the long‐term mean (and even when the amplitude is as small as 3 cm2/s, as obtained for a long‐term mean of 20 cm2/s), the amplitude of the salinity variation near regions of strong mixing is smaller than but on the same order of magnitude as that observed. The induced salinity anomaly spreads broadly, over a distance of several hundreds of kilometers, by mean currents with a short lag time of less than 3 years, and is suggested to influence the model winter mixed layer over broad regions. These results support the hypothesis stated above and suggest that it is necessary to clarify spatial and temporal variations in tidal mixing to reproduce both the mean states of and temporal variations in water masses of the subarctic North Pacific.
African/Amazonian Proterozoic correlations of Iberia: A detrital zircon U‐Pb study of early Cambrian conglomerates from the Sierra de la Demanda (northern Spain)
Authors: Ábalos B. , Gil Ibarguchi J. I. , Sánchez‐Lorda M. E. , Paquette J. L.
Published: March 2012

Unfoliated conglomerates define the base of an Early Cambrian transgressive system tract in the Sierra de la Demanda. Correlations allow us to bracket the corresponding sechron between 532 Ma and 520–521 Ma. These conglomerates contain sandstone and metamorphic quartzite pebbles carrying detrital tourmaline, rutile and zircon grains of plutonic or medium‐ to high‐grade metamorphic derivation. Zircon detrital grains exhibit concordant or sub‐concordant U/Pb ages clustered in various groups, including Neoarchean (2.52–2.56 Ga), Paleoproterozoic (1.71–2.02 Ga), and Mesoproterozoic (1.47 and ca. 1.1–1.0 Ga), the latter representative of orogenic magmatism related to Rodinia supercontinental assembly. The Neoproterozoic is represented by concordant ages in the range 750–880 Ma and by Cryogenian discordant ages. Ediacaran zircons cluster in two subsets ranging between 590 and 680 Ma and 560–585 Ma, both including several concordant ages. They reflect formation of juvenile crust in magmatic arc and back‐arc basin settings. Zircon ages younger than 520–525 Ma postdate the depositional age of the conglomerate and may represent Hercynian overprinting. Bibliographic data overlooked in other provenance studies indicate that Mesoproterozoic relics as those presented here should no longer be considered of exotic origin with respect to a Gondwanan (West African) affinity of the Neoproterozoic to early Paleozoic of Iberia. The proposed source area, the “Ebro Massif” of central‐north Iberia, currently is concealed under a kilometer‐thick Paleozoic or younger cover. Its tectonic organization would compare to that of the North African or Amazonian cratons (including Mesoproterozoic components), rather than to the Neoproterozoic arc settings described in northwest and southwest Iberia.
A low‐cost method to measure the timing of postfire flash floods and debris flows relative to rainfall
Authors: Kean Jason W. , Staley Dennis M. , Leeper Robert J. , Schmidt Kevin M. , Gartner Joseph E.
Published: March 2012

Data on the specific timing of postfire flash floods and debris flows are very limited. We describe a method to measure the response times of small burned watersheds to rainfall using a low‐cost pressure transducer, which can be installed quickly after a fire. Although the pressure transducer is not designed for sustained sampling at the fast rates (≤2 s) used at more advanced debris flow monitoring sites, comparisons with high‐frequency stage data show that measured spikes in pressure sampled at 1 min intervals are sufficient to detect the passage of most debris flows and floods. Postevent site visits are used to measure the peak stage and identify flow type on the basis of deposit characteristics. The basin response time scale (tb) to generate flow at each site was determined from an analysis of the cross correlation between time series of flow pressure and 5 min rainfall intensity. This time scale was found to be less than 30 min for 40 postfire floods and 11 postfire debris flows recorded in 15 southern California watersheds (≤1.4 km2). Including data from 24 other debris flows recorded at 5 more instrumentally advanced monitoring stations, we find there is not a substantial difference in the median tb for floods and debris flows (11 and 9 min, respectively); however, there are slight, statistically significant differences in the trends of flood and debris flow tb with basin area, which are presumably related to differences in flow speed between floods and debris flows.
Global CO2 distributions over land from the Greenhouse Gases Observing Satellite (GOSAT)
Authors: Hammerling Dorit M. , Michalak Anna M. , O'Dell Christopher , Kawa S. Randolph
Published: March 2012

January 2009 saw the successful launch of the first space‐based mission specifically designed for measuring greenhouse gases, the Japanese Greenhouse gases Observing SATellite (GOSAT). We present global land maps (Level 3 data) of column‐averaged CO2 concentrations (XCO2) derived using observations from the GOSAT ACOS retrieval algorithm, for July through December 2009. The applied geostatistical mapping approach makes it possible to generate maps at high spatial and temporal resolutions that include uncertainty measures and that are derived directly from the Level 2 observations, without invoking an atmospheric transport model or estimates of CO2uptake and emissions. As such, they are particularly well suited for comparison studies. Results show that the Level 3 maps for July to December 2009 on a 1° × 1.25° grid, at six‐day resolution capture much of the synoptic scale and regional variability of XCO2, in addition to its overall seasonality. The uncertainty estimates, which reflect local data coverage, XCO2variability, and retrieval errors, indicate that the Southern latitudes are relatively well‐constrained, while the Sahara Desert and the high Northern latitudes are weakly‐constrained. A probabilistic comparison to the PCTM/GEOS‐5/CASA‐GFED model reveals that the most statistically significant discrepancies occur in South America in July and August, and central Asia in September to December. While still preliminary, these results illustrate the usefulness of a high spatiotemporal resolution, data‐driven Level 3 data product for direct interpretation and comparison of satellite observations of highly dynamic parameters such as atmospheric CO2.
A 1‐year longδ18O record of water vapor in Niamey (Niger) reveals insightful atmospheric processes at different timescales
Authors: Tremoy Guillaume , Vimeux Françoise , Mayaki Salla , Souley Ide , Cattani Olivier , Risi Camille , Favreau Guillaume , Oi Monique
Published: March 2012

We present a 1‐year long representativeδ18O record of water vapor (δ18Ov) in Niamey (Niger) using the Wavelength Scanned‐Cavity Ring Down Spectroscopy (WS‐CRDS). We explore how local and regional atmospheric processes influenceδ18Ov variability from seasonal to diurnal scale. At seasonal scale, δ18Ovexhibits a W‐shape, associated with the increase of regional convective activity during the monsoon and the intensification of large scale subsidence North of Niamey during the dry season. During the monsoon season,δ18Ovrecords a broad range of intra‐seasonal modes in the 25–40‐day and 15–25‐day bands that could be related to the well‐known modes of the West African Monsoon (WAM). Strongδ18Ovmodulations are also seen at the synoptic scale (5–9 days) during winter, driven by tropical‐extra‐tropical teleconnections through the propagation of a baroclinic wave train‐like structure and intrusion of air originating from higher altitude and latitude.δ18Ovalso reveals a significant diurnal cycle, which reflects mixing process between the boundary layer and the free atmosphere during the dry season, and records the propagation of density currents associated with meso‐scale convective systems during the monsoon season.
Along‐dip seismic radiation segmentation during the 2007 Mw 8.0 Pisco, Peru earthquake
Authors: Sufri Oner , Koper Keith D. , Lay Thorne
Published: March 2012

The short‐period (0.5–2 s) seismic radiation properties of the August 15 (23:40:57 UTC) 2007 Mw8.0 Pisco, Peru earthquake are imaged by back‐projecting P waves recorded at 374 elements of USArray deployed in western North America at distances of 54°–74° from the source region. The coherent short‐period seismic energy release has two main intervals similar to moment‐rate functions determined by inversion of longer‐period teleseismic body waves; however, the spatial locations of the coherent bursts of short‐period energy release are located north and down‐dip of the region of major slip. The contrast between short‐ and long‐period seismic radiation properties of the Pisco earthquake is more subtle than for the 2011 Mw9.0 Tohoku earthquake, but provides further support for the idea of depth‐dependent changes in sliding behavior during megathrust ruptures.
Small repeating earthquake activity, interplate quasi‐static slip, and interplate coupling in the Hyuga‐nada, southwestern Japan subduction zone
Authors: Yamashita Yusuke , Shimizu Hiroshi , Goto Kazuhiko
Published: March 2012

Small repeating earthquake (RE) analysis is a useful method for estimating interplate quasi‐static slip, which is a good indicator of interplate coupling. We detected 170 continual‐type interplate RE groups and then estimated the spatial variation in quasi‐static slip in the Hyuga‐nada over the past 17 years. The RE activity in this region has different characteristics compared with that in the northeast Japan subduction zone, presumably reflecting differences in the subduction properties. Our results revealed that interplate coupling spatially changes along the trench‐axis and dip‐direction—a phenomenon that cannot be resolved by land‐based Global Positioning System (GPS) analysis. By comparing seismicity, the low‐slip‐rate areas correspond with the location of hypocenters and asperities for large‐ and moderate‐sized interplate earthquakes, suggesting strong interplate coupling at these sites. These results indicate that the slip rate distribution estimated from RE activity is reliable and useful for assessing the potential of future large earthquakes.
Global simulation of proton precipitation due to field line curvature during substorms
Authors: Gilson M. L. , Raeder J. , Donovan E. , Ge Y. S. , Kepko L.
Published: March 2012

The low latitude boundary of the proton aurora (known as the Isotropy Boundary or IB) marks an important boundary between empty and full downgoing loss cones. There is significant evidence that the IB maps to a region in the magnetosphere where the ion gyroradius becomes comparable to the local field line curvature. However, the location of the IB in the magnetosphere remains in question. In this paper, we show simulated proton precipitation derived from the Field Line Curvature (FLC) model of proton scattering and a global magnetohydrodynamic simulation during two substorms. The simulated proton precipitation drifts equatorward during the growth phase, intensifies at onset and reproduces the azimuthal splitting published in previous studies. In the simulation, the pre‐onset IB maps to 7–8 RE for the substorms presented and the azimuthal splitting is caused by the development of the substorm current wedge. The simulation also demonstrates that the central plasma sheet temperature can significantly influence when and where the azimuthal splitting takes place.
TTC7B Emerges as a Novel Risk Factor for Ischemic Stroke Through the Convergence of Several Genome-Wide Approaches
Authors: Krug Tiago , Gabriel João Paulo , Taipa Ricardo , Fonseca Benedita V , Domingues-Montanari Sophie , Fernandez-Cadenas Israel , Manso Helena , Gouveia Liliana O , Sobral João , Albergaria Isabel , Gaspar Gisela , Jiménez-Conde Jordi , Rabionet Raquel , Ferro José M , Montaner Joan , Vicente Astrid M , Silva Mário Rui , Matos Ilda , Lopes Gabriela , Oliveira Sofia A
Published: March 2012

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5–intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.
Prevention of Acute/Severe Hypoglycemia-Induced Neuron Death by Lactate Administration
Authors: Won Seok Joon , Jang Bong Geom , Yoo Byung Hoon , Sohn Min , Lee Min Woo , Choi Bo Young , Kim Jin Hee , Song Hong Ki , Suh Sang Won
Published: March 2012

Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD+), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD+ affords neuroprotection against hypoglycemia-induced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by ∼80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD+ due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels.
Cocaine self-administration in the mouse: A low-cost, chronic catheter preparation
Authors: Pomrenze Matthew , Baratta Michael , Cadle Brian , Cooper Donald
Published: March 2012

Intravenous drug self-administration is the most valid animal model of human addiction because it allows volitional titration of the drug in the blood based on an individual’s motivational state together with the pharmacokinetic properties of the drug. Here we describe a reliable low-cost mouse self-administration catheter assembly and protocol that that can be used to assess a variety of drugs of abuse with a variety of protocols. We describe a method for intravenous catheter fabrication that allows for efficient and long-lasting intravenous drug delivery. The intravenous catheters remained intact and patent for several weeks allowing us to establish stable maintenance of cocaine acquisition. This was followed by a dose response study in the same mice. For collaborators interested in premade catheters for research please make a request at www.neuro-cloud.net/nature-precedings/pomerenze.
Simple Drugs Do Not Cure Complex Diseases: The Need for Multi-Targeted Drugs
Authors: Hornberg Jorrit J.
Published: March 2012

Systems biology has shown that the multi-factorial nature of complex disease networks and their intrinsic robustness against perturbation makes the rational design of multi-targeted drugs essential. Simple drugs cannot cure complex diseases. In both cancer and rheumatoid arthritis, highly complex networks are affected and many different cell types are involved. In cancer, disturbance of signal transduction leads to the evasion of apoptosis and growth control, and the induction of angiogenesis and metastasis. The key signalling pathways in inflammation are similar to those involved in cancer. Multiple factors, such as kinases, are involved in activating signalling pathways downstream from the T-cell receptor. Though polypharmacology is often associated with side effects, multi-targeted drugs when rationally designed can have a larger therapeutic window than those hitting a single target if the therapeutic effects overlap but the detrimental effects do not.
Phenotypic and In Vivo Screening: Lead Discovery and Drug Repurposing
Authors: Lipinski Christopher A.
Published: March 2012

The changes in screening philosophy over a 40 year period from in vivo phenotypic screening to a reductionist mechanism-based in vitro search for a single selective compound against a single target are described. Examples are given of the shortcomings of the reductionist paradigm and the advantages of the phenotypic and multi-target screening approaches towards drug discovery and repurposing. Non-mechanism biased phenotypic screening offers the advantages of enhanced target opportunity space and is a good match for screening of ligands covering narrow chemistry space, e.g. natural products. Retrospective analysis suggests that phenotypic screening is better than mechanistic screening in finding first in class compounds, particularly for the more complex disease targets.
Historical Strategies for Lead Generation
Authors: Richard Morphy J.
Published: March 2012

An increasing number of lead generation approaches are being applied to multi-target drug discovery (MTDD). Historically, focussed screening and a knowledge-based approach called framework combination have been most widely used – with varying degrees of success. More recently, alternative screening approaches such as HTS, fragment-based screening and in silico screening are being used alongside the traditional approaches in order to discover novel hits with attractive physicochemical and oral pharmacokinetic properties. Factors influencing the feasibility of discovering DMLs for particular combinations are discussed in this chapter. The role of natural products and the discovery of probes for chemical biology are also highlighted.
The Discovery of Lapatinib
Authors: Lackey Karen E.
Published: March 2012

Protein kinases are now considered highly druggable due to the fact that there are kinase inhibitors on the market as effective drugs (e.g. Gleevec, Tarceva, and Nexavar). The class of drugs remains plagued by questions about how the inhibition profile affects the efficacy, and whether truly selective kinase inhibitors actually exist. Lapatinib remains one of the most selective kinase inhibitors in use for cancer therapy. This chapter will focus on our strategies to discover this novel, dual EGFR and ERBB-2 tyrosine kinase inhibitor using a carefully designed biological evaluation cascade coupled with a multidimensional data analysis. The primary topics discussed will cover the optimization of potency for two kinase targets, yet selective among over 500 kinases within the highly homologous ATP binding site, cellular selectivity and efficacy, and subsequent studies to understand the mechanism of action.
Identification and Optimization of Dual PI3K/mTOR Inhibitors
Authors: Karlsson Andreas , García-Echeverría Carlos
Published: March 2012

The constitutive activation of the PI3K/mTOR pathway in cancer cells has been validated by epidemiological and experimental studies as an essential step towards the initiation and maintenance of human tumors. A number of intracellular components of this pathway have been targeted for anti-cancer drug discovery activities leading to the current panoply of clinical trials of PI3K/mTOR pathway modulators. The progress in the identification and development of early polypharmacology-based inhibitors that concomitantly target PI3K and mTOR is presented and discussed in this chapter.
Discovery of HDAC-Inhibiting Multi-Target Inhibitors
Authors: Cai Xiong , Qian Changgeng
Published: March 2012

Several HDAC-inhibiting multiple-target inhibitors have been reported. In this chapter, the current progress in investigating HDAC-inhibiting multi-target inhibitors is briefly reviewed, with a focus on the first and only clinical candidate CUDC-101 as the case study example. CUDC-101 is a novel small molecule potently inhibiting activities of the EGFR and HER2 kinases and HDAC enzymes with IC50 values of 2.4, 15.7, and 4.4nM, respectively. CUDC-101's rational design and synthesis, superior in vitro potency, broad anti-proliferative and pro-apoptotic activities in cultured tumor cells including RTK inhibitor-resistant cell lines, effective network disruption in survival signaling pathways, high efficacy in in vivo xenograft animal models, favorable safety profile, and preliminary evidence of anti-tumor activity in phase I trials are presented in this chapter. This case study provides proof-of-principle that a single molecule with multiple targeted specificities can improve the effectiveness of current anticancer therapeutics preclinically.
Discovery of the Anti-Psychotic Drug, Ziprasidone
Authors: Lowe, III John A.
Published: March 2012

There is no better illustration of the principles of multi-target drug discovery than the field of antipsychotic medicinal chemistry. The first antipsychotic agents, discovered serendipitously in clinical testing, possess a plethora of pharmacological activity, primarily as antagonists of neurotransmitter receptors. Thus in selecting a pharmacological profile for a second-generation antipsychotic to address the side effects of these first drugs, we had many choices to make, settling on a combination of D2 dopamine and 5HT2 serotonin receptor blockade. Our strategy led us to a series of oxindoles linked to benzisothiazolyl piperazine, from which we selected ziprasidone as a novel atypical antipsychotic agent for clinical trials. Ziprasidone's favorable ratio of 5HT2 to D2 receptor affinity affords antipsychotic efficacy with low side effect propensity, including a weight neutral profile. Exploiting a multi-target strategy produced a successful atypical antipsychotic that benefits patients in over 80 countries worldwide.
The Preparation, Optimization and Characterization of Viral Protein Complexed Liposomes.
Authors: Tiwari Shailja , Verma Sunil K , Vyas Suresh P.
Published: March 2012

The present study is aimed at exploiting the potential of liposomal nanomedicines in the design of an intranasal HBsAg vaccine and describes the preparation, optimization and characterization of the same. In order to enhance the nasal uptake of the liposomal carrier the mucosal M cell binding protein haemagglutinin (HA) from the influenza virus was complexed onto the liposomal surface. The liposomal formulations were prepared by the dehydration-rehydration-vesiculation method. They were optimized and characterized for various in vitro parameters and the optimized liposomal formulations were again selected for the conjugation of HA on to its surface by the carbodimide coupling method. Initially, the formulations were prepared and various process and parameters that could affect the preparation and properties of the system(s) were identified, characterized and studied.
The Phase Behaviour of Saturated and Unsaturated Monoglycerides and the Influence of Triglyceride on the Aggregation in Hydrophobic System
Authors: Alfutimie A. , Curtis R. , Tiddy G.J.T.
Published: March 2012

It is well known that long chain monoglycerides form a metastable α-gel phase (Lβ) on cooling. Despite the inevitable storage problems, this state is frequently employed to stabilise emulsions or to incorporate “active” ingredients in many food and fragrance applications, and is also used for drug delivery. In this work, we have examined the phase behaviour of saturated and unsaturated monoglyceride. Furthermore, the same systems have been studied in mixtures containing liquid triglycerides. In the study, Optical microscopy has been employed as a function of temperature for an initial survey of phase behaviour, and differential scanning calorimetry (DSC) has been used to determine the transition temperatures and enthalpies between mesophases. Surfactant mobility in the various phases was studied by measuring proton nuclear magnetic resonance (NMR) T2 relaxation times in order to characterize the solid phase fraction in the sample. In parallel, small angle X-ray scattering (SAXS) and wide angle X-ray scattering (WAXS) have been used to identify the structures of the different mesomorphic phases formed at different temperatures. The study shows various ordered phases are formed by glycerol monostearate (GMS), GMS/oil, glycerol monooleate (GMO), GMO/oil. There are 4 phases associated with GMS, α–gel phase, sub α phase, L2 and β3 crystal. However, when oil is added 5 phases are seen, α–gel phase, sub α phase, β2 crystal, L2 and β3 crystal .Only 2 phases are found for GMO, β1 crystal and L2, while for GMO/oil 3 phases are found, β2 crystal, β1 crystal and L2 . Furthermore, this paper proves that the oil incorporates with sub α phase and α gel phase for GMS, and this is not the case for GMO.
Formulation of Gliclazide Encapsulated Chitosan Nanoparticles: In Vitro and In Vivo Evaluation
Authors: Averineni Ranjith Kumar , Shavi Gopal Venkatesh , Ranjan Om Prakash , Balavant Deshpande Praful , Aravind Kumar Gurram , Yogendra Nayak Usha , Sreenivasa Reddy Meka , Udupa Nayanabhirama
Published: March 2012

The aim of this study was to formulate and evaluate gliclazide (GLC) loaded chitosan nanoparticles (NP's). GLC is a hypoglycemic agent, stimulates insulin secretion from functional pancreatic beta-cells and increases the sensitivity of the beta cells to glucose. In the present study GLC loaded chitosan NP's were prepared by salting out of chitosan with sodium citrate. The influence of various formulation factors (stirring speed, drug: polymer ratio) on particle size, drug loading, and encapsulation efficiency were investigated. The particle size analysis was determined by dynamic light scattering technique. The developed NP's showed high drug loading and encapsulation efficiency. FT-IR and DSC studies showed no interaction of GLC with polymers. The release of drug from NP's exhibited over a period of 24 h with an initial burst effect followed by sustained release. The rate and amount of the drug release was decreased as the polymer content increased. The optimum ratio was found to be 1:2.5 with high encapsulation efficiency with sustained drug release. Stability studies revealed that the GLC-loaded NP's were stable for the period of three months.
The Effect of Formulation and Process Variables on Droplet Size Reduction using a High-throughput Processing Platform
Authors: Riding Vicky , Harvey Daniel , Martin Peter J. , Kowalski Adam J.
Published: March 2012

The performance, shelf-life & consumer appeal of formulated chemical products is partly a consequence of the formulation and partly due to the internal micro structure created during manufacture. Increasing competition, shorter product life-cycle times as well as opportunities for new & sustainable technologies demand an increased innovation rate and greater time, energy & materials efficiencies to create products that address the unmet needs of consumers whilst controlling cost & environmental impact.

In this area of science where Chemistry meets Chemical Engineering; a novel, laboratory-scale, commercial, high throughput processing platform the Chemspeed Formax, was used to investigate the effect of formulation and process variables on droplet size reduction.

A design of experiment (DOE) method utilised: a range of silicone oils, water & surfactant (SLES) of various proportions, a range of stirring speeds & durations and two different stirrer geometries (rotor stator & saw-tooth impeller). The relationship between droplet size and power input for each were compared.

This assessment of the potential for emulsion creation is useful for formulators involved in product development and improved stability preparations. Comparison of results from this small scale mixing equipment with larger mixers is useful for manufacturers with respect to product scale-up.
Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP
Authors: Dong Xue-Yuan , Fu Xiaoying , Fan Songqing , Guo Peng , Su Dan , Dong Jin-Tang
Published: March 2012

We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen–ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen–ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin–proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen–ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.