bluuebunny/crossref_metadata_2025_split huggingface dataset:
Docking studies to explore novel inhibitors against human beta-site APP cleaving enzyme (BACE-1) involved in Alzheimer’s disease
Authors: Anjum Mobeen S , Munikumar Manne , Umamaheswari Amineni 
Published: March 2012

AbstractAlzheimer’s disease (AD) is one of the most prominent neurodegenerative disorders, particularly in elder persons over 65 age. It is characterized by progressive cognitive deterioration together with declining activities. Amyloid precursor protein (APP) cleaves at A-beta (Aβ) peptide by rate limiting factor of Beta-site APP cleaving enzyme (BACE-1) in amyloidogenic pathway. Elevated level of BACE-1 leads to the accumulation of an insoluble form of Aβ peptides (Senile Plaques), an important hallmark in the pathogenesis of Alzheimer disease. Five published inhibitors of BACE-1, thiazolidinediones, rosiglitazone, pioglitazone, Sc7 and tartaric acid are available with poor pharmacological properties and intolerable side effects. Therefore, a computational approach was undertaken to design novel inhibitors against human BACE-1. The crystal structure of human BACE-1 was retrieved from the protein data bank and optimized by applying OPLS force field in Maestro v9.2. An ASINEX database (115,000 ligands) was downloaded and compounds were prepared using LigPrep. The optimized ligand dataset was docked into the BACE-1 through sequential application of Glide HTVS, SP and XP methods that penalizes more stringently for minor steric classes subsequently. Finally, seven leads were reported and ranked based on XPGscore with better binding affinity and good pharmacological properties compared with existing inhibitors. Six leads were proposed for human BACE-1. Among the six, lead 1, with XPGscore -8.051Kcal/mol, would be intriguing for rational drug design against Alzheimer’s disease and would be highly encouraging for future Alzheimer’s therapy if tested in animal models.
Isotope composition and volume of Earth’s early oceans
Authors: Pope Emily C. , Bird Dennis K. , Rosing Minik T. 
Published: March 2012

Oxygen and hydrogen isotope compositions of Earth’s seawater are controlled by volatile fluxes among mantle, lithospheric (oceanic and continental crust), and atmospheric reservoirs. Throughout geologic time the oxygen mass budget was likely conserved within these Earth system reservoirs, but hydrogen’s was not, as it can escape to space. Isotopic properties of serpentine from the approximately 3.8 Ga Isua Supracrustal Belt in West Greenland are used to characterize hydrogen and oxygen isotope compositions of ancient seawater. Archaean oceans were depleted in deuterium [expressed as
δ
D relative to Vienna standard mean ocean water (VSMOW)] by at most 25 ± 5‰, but oxygen isotope ratios were comparable to modern oceans. Mass balance of the global hydrogen budget constrains the contribution of continental growth and planetary hydrogen loss to the secular evolution of hydrogen isotope ratios in Earth’s oceans. Our calculations predict that the oceans of early Earth were up to 26% more voluminous, and atmospheric CH
4
and CO
2
concentrations determined from limits on hydrogen escape to space are consistent with clement conditions on Archaean Earth.
Fish Species of Greatest Conservation Need in Wadeable Iowa Streams: Current Status and Effectiveness of Aquatic Gap Program Distribution Models
Authors: Sindt Anthony R. , Pierce Clay L. , Quist Michael C. 
Published: March 2012

Abstract
Effective conservation of fish species of greatest conservation need (SGCN) requires an understanding of species–habitat relationships and distributional trends. Thus, modeling the distribution of fish species across large spatial scales may be a valuable tool for conservation planning. Our goals were to evaluate the status of 10 fish SGCN in wadeable Iowa streams and to test the effectiveness of Iowa Aquatic Gap Analysis Project (IAGAP) species distribution models. We sampled fish assemblages from 86 wadeable stream segments in the Mississippi River drainage of Iowa during 2009 and 2010 to provide contemporary, independent fish species presence–absence data. The frequencies of occurrence in stream segments where species were historically documented varied from 0.0% for redfin shiner Lythrurus umbratilis to 100.0% for American brook lamprey Lampetra appendix, with a mean of 53.0%, suggesting that the status of Iowa fish SGCN is highly variable. Cohen's kappa values and other model performance measures were calculated by comparing field-collected presence–absence data with IAGAP model–predicted presences and absences for 12 fish SGCN. Kappa values varied from 0.00 to 0.50, with a mean of 0.15. The models only predicted the occurrences of banded darter Etheostoma zonale, southern redbelly dace Phoxinus erythrogaster, and longnose dace Rhinichthys cataractae more accurately than would be expected by chance. Overall, the accuracy of the twelve models was low, with a mean correct classification rate of 58.3%. Poor model performance probably reflects the difficulties associated with modeling the distribution of rare species and the inability of the large-scale habitat variables used in IAGAP models to explain the variation in fish species occurrences. Our results highlight the importance of quantifying the confidence in species distribution model predictions with an independent data set and the need for long-term monitoring to better understand the distributional trends and habitat associations of fish SGCN.
Received April 16, 2011; accepted November 19, 2011
Highly ordered nanoscale surface ripples produced by ion bombardment of binary compounds
Authors: Motta Francis C , Shipman Patrick D , Bradley R Mark 
Published: March 2012

Abstract
Nanoscale surface ripples generated by oblique-incidence ion bombardment of a solid are generally full of defects, and this has prevented the widespread adoption of ion bombardment as a nanofabrication tool. We advance a theory that predicts that remarkably defect-free ripples can be produced by ion bombardment of a binary material if the ion species, energy and angle of incidence are appropriately chosen. This high degree of order results from the coupling between the surface height and composition, and cannot be achieved by bombarding an elemental material.
Pump–probe photothermal spectroscopy using quantum cascade lasers
Authors: Farahi R H , Passian A , Tetard L , Thundat T 
Published: March 2012

Abstract
Obtaining compositional information for objects from a distance remains a major challenge in chemical and biological sensing. Capitalizing on mid-infrared (IR) excitation of molecules by using quantum cascade lasers (QCLs) and invoking a pump–probe technique, we present a variation of the photothermal process that can provide spectral fingerprints of substances from a variable standoff distance. We have evaluated the modal variations of the QCL beam that must be taken into account when applying QCLs for photothermal measurements. The results compare well with spectra obtained from conventional IR spectroscopy. Guided by the results, the potential of the measurements to be extended such that each point within a target region may be spectrally interrogated to form a hyperspectral image is discussed.
Nanoscale stoichiometric modifications and surface charge patterning of La1.975Sr0.025CuO4+δ crystals with a biased atomic force microscope tip
Authors: Strojnik M , Strle J , Jenko M , Mihailovic D 
Published: March 2012

Abstract
The application of a positive or negative local bias to the surface of La1.975Sr0.025CuO4+δ (LSCO) crystal by a conducting atomic force microscope tip results in accumulation of a (positive or negative, respectively) metastable charge on the surface. The surface charge initially shows diffusive dynamics with a timescale of hours, but thereafter it is shown to be stable for months. The charged regions are found by Auger electron spectroscopy to have a different stoichiometry from the surrounding material. Apart from fundamental implications for the heterostructure device construction, such surface charge manipulation could lead to AFM nanopatterning of superconducting nanoscale devices and applications in memories.
A novel A20 (TNFAIP3) antibody (Ber‐A20) can be used to detect unmutated A20 by immunohistology
Authors: Hirsch Burkhard , Grünbaum Maria , Wagner Florian , Bi Yingwen , Lucka Lothar , Du Ming‐Qing , Stein Harald , Dürkop Horst 
Published: March 2012

Hirsch B, Grünbaum M, Wagner F, Bi Y, Lucka L, Du M‐Q, Stein H & Dürkop H(2012) Histopathology 60, E19–E27A novel A20 (TNFAIP3) antibody (Ber‐A20) can be used to detect unmutated A20 by immunohistologyAims:  A20 (TNFAIP3) is a nuclear factor‐κB (NF‐κB)‐inducible component of tumour necrosis factor and Toll‐like receptor intracellular signal transduction. It negatively regulates NF‐κB, and has been identified as a tumour suppressor. Several studies have described A20 inactivation by deletion of the A20 locus at 6q23, inactivating mutations, and/or methylation of the A20 promoter in various lymphoma entities.Methods and results:  We generated a monoclonal antibody against the C‐terminus of A20 (Ber‐A20) and investigated full‐length A20 expression of normal lymphoid tissue and lymphomas for the first time. We identified loss of A20 expression in tumour cells of 24% of classical Hodgkin lymphoma, 27% of diffuse large B‐cell lymphoma, 20% of chronic lymphocytic leukaemia, 19% of follicular lymphoma, 13% of mantle cell lymphoma and 8% of primary mediastinal B‐cell lymphoma cases by immunohistology. Loss of A20 expression rarely occurred in T‐cell non‐Hodgkin lymphoma.Conclusions:  Our data are in agreement with cytogenetic and molecular analyses. Among 21 cases of ocular adnexal marginal zone lymphomas with known A20 mutation status, we detected complete absence of A20 expression, whereas cases with wild‐type A20 were weakly A20‐positive. We demonstrate that A20 loss can be detected by immunohistology with a sensitivity similar to that of complex molecular and genetic methods.
Antigenic fractions of Leishmania (Viannia) braziliensis: the immune response characterization of patients at the initial phase of disease
Authors: BRELAZ M. C. A. , De OLIVEIRA A. P. , De ALMEIDA A. F. , De ASSIS SOUZA M. , MEDEIROS Â. C. R. , De BRITO M. E. F. , PEREIRA V. R. A. 
Published: March 2012

SummaryAmerican cutaneous leishmaniasis (ACL) has different clinical manifestations and these manifestations are dependent on the immunological status of the host. As CD4+ and CD8+ T cells and their mediators play a fundamental role in the host response to Leishmania and there is also a search for antigenic molecules to be used as future vaccines and tools for prognostic tests, this study characterized ACL patients’ immune response after stimulation with soluble and insoluble fractions of L. (V.) braziliensis. We demonstrated a prevailing production of the Th2 cytokines, IL‐4 and IL‐10 and a specific production of IFN‐γ and TNF‐α in patients before treatment. There was also a predominance of CD4+ T cells and a small percentage CD8+ T cells. The insoluble antigenic fraction primarily stimulated CD4+ T cells, while the soluble antigenic fraction showed a mixed profile, with CD4+ T cells being the main responsible for Th2 cytokines and CD8+ T cells for Th1 cytokines. Therefore, our results showed that a down‐modulation of the Th1 type of response occurs in the initial phase of L. braziliensis disease, being the antigenic fractions capable of stimulating a specific immune response.
Withania somnifera chemotypes NMITLI 101R, NMITLI 118R, NMITLI 128R and withaferin A protect Mastomys coucha from Brugia malayi infection
Authors: KUSHWAHA S. , SONI V. K. , SINGH P. K. , BANO N. , KUMAR A. , SANGWAN R. S. , MISRA‐BHATTACHARYA S. 
Published: March 2012

SummaryWithania somnifera is an ayurvedic Indian medicinal plant whose immunomodulatory activities have been widely used as a home remedy for several ailments. We recently observed immunostimulatory properties in the root extracts of chemotypes NMITLI‐101, NMITLI‐118, NMITLI‐128 and pure withanolide, withaferin A. In the present study, we evaluated the potential immunoprophylactic efficacies of these extracts against an infective pathogen. Our results show that administration of aqueous ethanol extracts (10 mg/kg) and withaferin A (0·3 mg/kg), 7 days before and after challenge with human filarial parasite Brugia malayi, offers differential protection in Mastomys coucha with chemotype 101R offering best protection (53·57%) as compared to other chemotypes. Our findings also demonstrate that establishment of B. malayi larvae was adversely affected by pretreatment with withaferin A as evidenced by 63·6% reduction in adult worm establishment. Moreover, a large percentage of the established female worms (66·2%) also showed defective embryogenesis. While the filaria‐specific immunological response induced by withaferin A and NMITLI‐101 showed a mixed Th1/Th2 phenotype, 118R stimulated production of IFN‐γ and 128R increased levels of IL‐4. Taken together, our findings reveal potential immunoprophylactic properties of W. somnifera, and further studies are needed to ascertain the benefits of this plant against other pathogens as well.
Three Arabidopsis AIL/PLT genes act in combination to regulate shoot apical meristem function
Authors: Mudunkothge Janaki S. , Krizek Beth A. 
Published: March 2012

SummaryThe shoot apical meristem, a small dome‐shaped structure at the shoot apex, is responsible for the initiation of all post‐embryonic shoot organs. Pluripotent stem cells within the meristem replenish themselves and provide daughter cells that become incorporated into lateral organ primordia around the meristem periphery. We have identified three novel regulators of shoot apical meristem activity in Arabidopsis thaliana that encode related AIL/PLT transcription factors: AINTEGUMENTA (ANT), AINTEGUMENTA‐LIKE6 (AIL6)/PLETHORA3 (PLT3) and AINTEGUMENTA‐LIKE7 (AIL7)/PLETHORA7 (PLT7). Loss of these genes results in plants that initiate only a few leaves prior to termination of shoot apical meristem activity. In 7‐day‐old ant ail6 ail7 seedlings, we observed reduced cell division in the meristem region, differentiation of meristematic cells and altered expression of the meristem regulators WUSCHEL (WUS), CLAVATA3 (CLV3) and SHOOT MERISTEMLESS (STM). Genetic experiments suggest that these three AIL genes do not act specifically in either the WUS/CLV or STM pathway regulating meristem function. Furthermore, these studies indicate that ANT, AIL6 and AIL7 have distinct functions within the meristem rather than acting in a strictly redundant manner. Our study thus identifies three new genes whose distinct functions are together required for continuous shoot apical meristem function.
Fair reckoning: a qualitative investigation of responses to an economic health resource allocation survey
Authors: Giacomini Mita , Hurley Jeremiah , DeJean Deirdre 
Published: March 2012

AbstractObjective  To investigate how participants in an economic resource allocation survey construct notions of fairness.Design  Qualitative interview study guided by interpretive grounded theory methods.Setting and participants  Qualitative interviews were conducted with volunteer university‐ (n = 39) and community‐based (n = 7) economic survey participants.Intervention or main variables studied  We explored how participants constructed meanings to guide or explain fair survey choices, focusing on rationales, imagery and additional desired information not provided in the survey scenarios.Main outcome measures  Data were transcribed and coded into qualitative categories. Analysis iterated with data collection iterated through three waves of interviews.Results  Participants compared the survey dilemmas to domains outside the health system. Most compared them with other micro‐level, inter‐personal sharing tasks. Participants raised several fairness‐relevant factors beyond need or capacity to benefit. These included age, weight, poverty, access to other options and personal responsibility for illness; illness duration, curability or seriousness; life expectancy; possibilities for sharing; awareness of other’s needs; and ability to explain allocations to those affected. They also articulated a fairness principle little considered by equity theories: that everybody must get something and nobody should get nothing.Discussion and conclusions  Lay criteria for judging fairness are myriad. Simple scenarios may be used to investigate lay commitments to abstract principles. Although principles are the focus of analysis and inference, participants may solve simplified dilemmas by imputing extraneous features to the problem or applying unanticipated principles. These possibilities should be taken into account in the design of resource allocation surveys eliciting the views of the public.
Comparison of adherence between twice‐ and thrice‐daily regimens of oral amoxicillin/clavulanic acid
Authors: LLOR CARL , BAYONA CAROLINA , HERNÁNDEZ SILVIA , MORAGAS ANA , MIRAVITLLES MARC 
Published: March 2012

ABSTRACTBackground and objective:  Few studies have analysed adherence with antibiotic treatment in patients with respiratory tract infections. The aim of this study was to compare the compliance of patients taking a pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid twice daily with that of patients taking the standard formulation thrice daily.Methods:  Patients with suspected bacterial lower respiratory tract infections, pharyngitis and dental infections were included. Adherence was assessed by electronic monitoring, which recorded every opening of the patient's bottle of pills. The outcome variables were compliance with taking the medication, taking the correct dose and with timing of the dose.Results:  A total of 240 patients were enrolled (167 in the thrice‐daily group and 73 in the twice‐daily group). The percentage of doses taken was greater with the twice‐daily regimen (84.5 ± 22.8%) than with the thrice‐daily regimen (72.7 ± 20.1%; P < 0.001). Forty patients in the twice‐daily group opened the container every 12 ± 6 h during at least 80% of the course (54.8%), while only 19.6% of the patients assigned to the thrice‐daily formulation did so every 8 ± 4 h (P < 0.001). The percentage of patients who opened the container a satisfactory number of times per day was significantly higher among those taking the twice‐daily regimen on days three, four, five, six and seven. Moreover, the thrice‐daily group more frequently forgot to take the afternoon dose.Conclusions:  The rate of compliance with amoxicillin/clavulanic acid therapy was very low. However, compliance with the new formulation that is taken twice‐daily was significantly better.
Both NKCC1 and anion exchangers contribute to Cl− accumulation in postnatal forebrain neuronal progenitors
Authors: Sun Lin , Yu Zhiyuan , Wang Wei , Liu Xiuxin 
Published: March 2012

AbstractNeuronal progenitors are continuously generated in the postnatal rodent subventricular zone and migrate along the rostral migratory stream to supply interneurons in the olfactory bulb. Nonsynaptic GABAergic signaling affects the postnatal neurogenesis by depolarizing neuronal progenitors, which depends on an elevated intracellular Cl− concentration. However, the molecular mechanism responsible for Cl− accumulation in these cells still remains elusive. Using confocal Ca2+ imaging, we found that GABA depolarization‐induced Ca2+ increase was either abolished by bumetanide, a specific inhibitor of the Na+–K+–2Cl− cotransporter, or reduced by partial replacement of extracellular Na+ with Li+, in the HEPES buffer but not in the CO2/ buffer. GABA depolarization‐induced Ca2+ increase in CO2/ buffer was abolished by a combination of bumetanide with the anion exchanger inhibitor DIDS or with the carbonic anhydrase inhibitor acetozalimide. Using gramicidin‐perforated patch‐clamp recording, we further confirmed that bumetanide, together with DIDS or acetozalimide, reduced the intracellular chloride concentration in the neuronal progenitors. In addition, with BrdU labeling, we demonstrated that blocking of the Na+–K+–2Cl− cotransporter, but not anion exchangers, reduced the proliferation of neuronal progenitors. Our results indicate that both the Na+–K+–2Cl− cotransporter and anion exchangers contribute to the elevated intracellular chloride responsible for the depolarizing action of GABA in the postnatal forebrain neuronal progenitors. However, the Na+–K+–2Cl− cotransporter displays an additional effect on neuronal progenitor proliferation.
The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis
Authors: Prell T. , Lautenschläger J. , Witte O. W. , Carri M. T. , Grosskreutz J. 
Published: March 2012

AbstractRecent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER–mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1G93A NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1G93A NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1G93A motor but not in wild‐type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time‐dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1G93A, providing evidence that ER stress plays a major role in ALS.
Reappraisal of the options for colorectal cancer screening in England
Authors: Whyte S. , Chilcott J. , Halloran S. 
Published: March 2012

AbstractAim  The aim was to use newly available data to estimate the cost effectiveness and endoscopy requirements of screening options for colorectal cancer (CRC) to inform screening policy in England.Methods  A state transition model simulated the life experience of a cohort of individuals in the general population of England with normal colon/rectal epithelium through to the development of adenomas and CRC and subsequent death. CRC natural history model parameters and screening test characteristics were estimated simultaneously by a process of model calibration. This process was fitted to observed data on CRC incidence in the absence of screening, data from existing screening programmes, and data from the UK flexible sigmoidoscopy (FS) screening trial. The costs, effects and resource impact were evaluated for a range of screening options involving the guaiac or immunochemical faecal occult blood test (gFOBT/iFOBT) and FS.Results  The model suggests that screening strategies involving FS or iFOBT may produce additional benefits compared with the current policy of biennial gFOBT for 60–74‐year‐olds. The age at which a single FS screen results in the greatest quality‐adjusted life year gain was 55, with similar gains for ages between 52 and 58. Strategies which combined FS and iFOBT showed further benefits and improved economic outcomes.Conclusions  Strategies which combine different screening modalities may provide greater clinical and economic benefits. The collection of comprehensive screening data using a uniform format will enable comparative analysis across screening programmes in different countries, will improve our understanding of the disease and will allow identification of optimal screening modalities.