bluuebunny/crossref_metadata_2025 huggingface dataset:
Selected Reference Works, 2007–081
Authors: Witte Sarah , Cargill Mary
Published: June 2014

This article follows the pattern set by the semiannual series initiated by the late Constance M. Winchell more than fifty years ago and continued first by Eugene Sheehy and then by Eileen McIlvaine. Because the purpose of the list is to present a selection of recent scholarly and general works, it does not pretend to be either well balanced or comprehensive. A brief roundup of new editions of standard works is provided at the end of the articles. Code numbers (such as AC527) have been used to refer to titles in the Guide to Reference Books, 11th ed. (Chicago: ALA, 1996).
Information Seeking through Students’ Eyes: The MIT Photo Diary Study
Authors: Gabridge Tracy , Gaskell Millicent , Stout Amy
Published: June 2014

In 2006, a team of librarians at MIT conducted a photo diary study of thirty-two students' academic information-seeking behaviors. The aim of this qualitative research approach, based on analyzing a week of student-generated photos and diary entries, was to understand how to design MIT's library systems and services to more effectively support students' information-seeking practices. The project generated data on 275 distinct information-seeking tasks used by the students. Examination of their goals, tasks and methods informed the MIT Libraries' priorities and planning efforts for improving library online systems in the following areas: improving discovery and search, incorporating trusted resources in finding tools and increasing links to library resources in external sites popular with the MIT community.
The Dreyfus Model of Skill Acquisition: A Career Development Framework for Succession Planning and Management in Academic Libraries
Authors: Hall-Ellis Sylvia D. , Grealy Deborah S.
Published: June 2014

Succession planning and management are critical parts of strategic planning for libraries in the twenty-first century. Making certain that the right people are in place with the prerequisite training and experience to assume leadership positions is a vital part of strategic planning and talent management in libraries that rely on teams of people working in flatter structures and greater accountability. The Dreyfus Model of Skill Acquisition framework suggests that mentoring, coaching, and professional development empower staff for movement up organizational career ladders as part of succession planning and management. To maximize human capital, administrators need to determine skill development levels among staff so that they can identify skill “gaps” internally, create new career ladders, identify emerging stars, and enhance evidence of values for staff contributions.
Peer Reviewers of Academic Journals: Who Is Responsible for Our Professional Literature
Authors: Francis Mary
Published: June 2014

Scholarly journals provide a record of the research, issues, and concerns of a field. Authors have their names associated with their individual articles, while editors are connected with a publication. However, there is another group of individuals who are often left out of the record, although their contributions are just as critical in the formation of scholarly journals. This article will take a look at this group of peer reviewers, to provide demographic data as well as understanding for the reasons individuals take on the duty of peer reviewer.
Relationships between Interlibrary Loan and Research Activity in Canada
Authors: Duy Joanna , Larivière Vincent
Published: June 2014

Interlibrary Loan borrowing rates in academic libraries are influenced by an array of factors. This article explores the relationship between interlibrary loan borrowing activity and research activity at 42 Canadian academic institutions. A significant positive correlation was found between interlibrary loan borrowing activity and measures of research activity. The degree of correlation observed depended on the category of institution, with undergraduate and comprehensive universities showing the largest correlations. This is the first study to quantify the relationship between interlibrary loan and research activity, and the findings suggest that interlibrary loan plays a role in supporting academic research at Canadian universities.
MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin
Authors: Yun Jina , Puri Rajat , Yang Huan , Lizzio Michael A , Wu Chunlai , Sheng Zu-Hang , Guo Ming
Published: June 2014

Parkinson's disease (PD) genes PINK1 and parkin act in a common pathway that regulates mitochondrial integrity and quality. Identifying new suppressors of the pathway is important for finding new therapeutic strategies. In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. The suppression is achieved through the ubiquitin-dependent degradation of Mitofusin, which itself causes PINK1/parkin mutant-like toxicity when overexpressed. We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone, leading to lethality in flies and degeneration in mouse cortical neurons. Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD.
High-resolution mapping reveals hundreds of genetic incompatibilities in hybridizing fish species
Authors: Schumer Molly , Cui Rongfeng , Powell Daniel L , Dresner Rebecca , Rosenthal Gil G , Andolfatto Peter
Published: June 2014

Hybridization is increasingly being recognized as a common process in both animal and plant species. Negative epistatic interactions between genes from different parental genomes decrease the fitness of hybrids and can limit gene flow between species. However, little is known about the number and genome-wide distribution of genetic incompatibilities separating species. To detect interacting genes, we perform a high-resolution genome scan for linkage disequilibrium between unlinked genomic regions in naturally occurring hybrid populations of swordtail fish. We estimate that hundreds of pairs of genomic regions contribute to reproductive isolation between these species, despite them being recently diverged. Many of these incompatibilities are likely the result of natural or sexual selection on hybrids, since intrinsic isolation is known to be weak. Patterns of genomic divergence at these regions imply that genetic incompatibilities play a significant role in limiting gene flow even in young species.
Value Investing: Bridging Theory and Practice
Authors: Lee Charles M. C.
Published: June 2014

Value investing refers to the buying or selling of stocks on the basis of a perceived gap between their current market price and their fundamental value – commonly defined as the present value of the expected future payoffs to shareholders. This style of investing is predicated upon two observations about publicly listed companies and their stock prices: (1) a share of stock is merely a fractional claim on the futures cash flows of an operating business, and that claim is the basis of its long-run value; (2) over shorter horizons, prices can deviate substantially from the long-run value of the stock. Value investors buy stocks that appear to be cheap relative to their intrinsic value and sell (even sell short) stocks that seem expensive.
LLFRP: An Energy Efficient Variant of LLF with Reduced Pre-emptions for Real – Time Systems
Authors: Baid Prashasti , Prashanth S , Raveendran Biju
Published: May 2014

Energy efficiency without performance degradation is a challenge in battery operated real-time systems. One way to achieve this is by optimizing scheduling parameters like preemptions and cache activities. In this work, we present an energy efficient variant of Least Laxity First scheduler – Least Laxity First with Reduced Preemptions – that reduces the number of preemptions in a schedule. We prove that our scheduler offers the same feasibility as LLF. We present extensive analysis through experimental results to show that our variant significantly reduces the number of preemptions. Our results also show that the number of preemptions in the schedule output by this algorithm is close to the minimum possible number. Our analysis addresses the following metrics: preemptions, cache impacts, decision points, response time, response time jitter, latency, time complexity and energy consumption. In this work the proposed algorithm is compared with dynamic priority scheduling algorithms like RM, EDF, nonstrict LLF and strict-LLF. The result shows that the proposed algorithm offers 4.25% of energy saving in comparison with EDF, RM and non-strict LLF and it offers 7% energy saving in comparison with strict-LLF. The result also shows that the proposed algorithm increases the scheduling utilization by 4% in comparison with EDF, RM and non-strict LLF and it increases scheduling utilization by 6% in comparison with strict-LLF.
Formulation and Evaluation of Oral Elementary Osmotic Pump Tablets of Sumatriptan Succinate
Authors: Pavani J. Kishan , Pavani S. , Kumar Y. Shravan , Venkatesh A. , Rao Y. Madhusudan
Published: May 2014

Aim: In the present study, Sumatriptan succinate was formulated as oral elementary osmotic pump with a zero-order drug release profile. Methodology: The effect of different formulation variables i.e. different types of osmogens, concentrations of osmogen and concentration of coating solution were studied. The in vitro evaluation was carried out in different release media. Result: Highest percentage of drug release was observed at high concentration of mannitol i.e., 1:3 (drug: mannitol). Osmogen with low osmotic pressure (38 atm) showed 71.01% zero-order drug release for 12 hours when compared to that of the osmogen with high osmotic pressure (356 atm) which showed 67.38% of release by zero order. Conclusion: Elementary osmotic pump tablets of Sumatriptan succinate were able to deliver zero-order release up to 12 hours independent of pH of dissolution media and have overcome the problem of chronotherapeutic effect.
Simple Controlled Release Delivery System for an Anti-hypertensive Drug via Buccal Route
Authors: Khattab Waleed M. , Gad Shadeed , El-Sayed Mohamed M. , Ghorab Mamdouh M.
Published: May 2014

Objective: This study aims to develop controlled release buccal tablets of losartan potassium based on bioadhesion using direct compression technique. Materials and Methods: The bioadhesive buccal tablets of losartan potassium were prepared after preliminary drug-excipients compatibility studies and micromeretics study for powder blends. The tablets were prepared by direct compression utilizing carbopol 934LR as a primary bioadhesive polymer either with or without chitosan or hydroxypropyl methylcellulose E15LV as secondary polymers. Other excipients included PVP K30 as a binder, magnesium stearate as a lubricant and mannitol as a diluent. The tablets were evaluated for weight variation, thickness and diameter, hardness, friability, drug content, surface pH, Ex-vivo residence time and bioadhesion force, In-vitro swelling and drug release study. The analysis of the release profiles in the light of distinct kinetic models (zero order, first order, Higuchi, Hixson-Crowell and Korsmeyer–Peppas) was carried out. Results and Discussion: The formula containing 40% w/w bioadhesive polymers of carbopol 934LR and chitosan (1:2) was selected as the optimum one based on a ranking methodology and then, it was subjected to Ex-vivo permeation and physical stability study in human saliva. Swelling index was 78.32±1.84% after 7h and tablets showed a neutral surface pH. Ex-vivo residence time was long enough for more than 10h. Ex-vivo bioadhesion force was 0.38±0.01N. Drug release was 57.64±3.43% after 8h following zero order kinetics with a steady state permeation flux of 0.959mg/cm2h. Tablets were physically stable in human saliva. Conclusion: These formulae improved, controlled and prolonged the release of losartan potassium from a buccal bioadhesive system for at least 8h in a simple way which can achieve a high patient compliance.
Temporal and spatial scales of a high‐flux electron disturbance in the cusp region: Cluster observations
Authors: Shi Jiankui , Zhang Ziying , Torkar Klaus , Dunlop Malcolm , Fazakerley Andrew , Cheng Zhengwei , Liu Zhenxing
Published: May 2014

Using the Cluster multispacecraft observations, we analyze a long‐duration field‐aligned high‐flux electron disturbance in the cusp region on 30 September 2001. All four Cluster spacecraft observed the same disturbance in which both the upward and downward electrons are observed and the electron flux was 1 order of magnitude higher than usual in the cusp. The temporal scale of the field‐aligned electron disturbance was at least 50 min. The spatial scale was about 540 km in the direction along the orbit and at least 1800 km in local time extent in the midaltitude cusp region. It was the longest duration and the largest spatial scale of any field‐aligned electron disturbance observed in the polar region up to date, and its observation would not have been possible with a single satellite. Both upward and downward electrons are the main contributors to the field‐aligned currents in the electron disturbance. During this electron disturbance, the solar wind dynamic pressure increased, and the interplanetary magnetic field (IMF) kept being southward. It is likely that the field‐aligned high‐flux electron disturbance with its long temporal and large spatial scales was caused by high dynamic pressure of the solar wind during a permanently southward IMF. This enables us to learn more about electron disturbances in the cusp and is important to understand the physical mechanism, especially for the solar wind‐magnetosphere‐ionosphere coupling.
Ionospheric response to the geomagnetic storm of 15 May 2005 over midlatitudes in the day and night sectors simultaneously
Authors: Galav Praveen , Rao S. S. , Sharma Shweta , Gordiyenko G. , Pandey Rajesh
Published: May 2014

The ionospheric response to the geomagnetic storm of 15 May 2005 has been studied over midlatitude stations in the dayside and nightside, simultaneously. In the day side the ionospheric response has been studied using the ground‐based GPS and ionosonde measurements from the stations POL2 and Alma‐Ata, respectively. The dayside total electron content (TEC) and foF2 variations are characterized by two well‐separated enhancements. Of which the first enhancement in both the parameters is attributed to the episode of prompt penetration electric field caused by the sudden southward turning of interplanetary magnetic field (IMF) Bz around 0600 UT. The second enhancement which was also superposed by wave like modulations has been attributed to the storm‐induced winds. The maximum peak‐to‐peak amplitude of modulation in TEC is found to be 5 TECU (total electron content unit, 1 TECU = 1016 el m−2). The enhanced plasma density observed during the daytime at midlatitudes is found to be locally produced and not transported from the equatorial ionization anomaly region because the time of enhanced plasma density at midlatitude is earlier than that observed at low latitudes. During the storm main phase, the nightside GPS observations from the midlatitude station ALGO (Algonquin Park, Canada) show moderate to large TEC fluctuations and short duration depletions that occur in a narrow latitude zone. These fluctuations and depletions in TEC have been attributed to the combined effect of storm‐induced equatorward movement of the midlatitude ionospheric trough due to the expansion of auroral oval and the storm time‐enhanced density. The maximum amplitude of the TEC depletions is found to be of the order of 20 TECU. Rate of TEC Index is also found to be high with a maximum value of 2.
Compensation of the Meyer‐Neldel Compensation Law for H diffusion in minerals
Authors: Jones Alan G.
Published: May 2014

The Meyer‐Neldel Rule (MNR), or compensation law, linearly relates the preexponent term to the logarithm of the excitation enthalpy for any process that is thermally driven in an Arrhenian manner, and MNR fits can be used to calibrate and validate laboratory experimental results. Both robust least squares linear regressions and nonrobust regressions on selected subsets for individual minerals with sufficient experimental data demonstrate that hydrogen diffusion in minerals obeys the MNR with differing MNR intercepts and gradients depending on the mineral. In particular, nominally anhydrous mantle minerals have very distinct and different MNR parameters compared to hydrous and crustal minerals, with garnet proving to be an outlier lying in between the two. Furthermore, the variations of the estimated intercepts and gradients of the various MNRs are not random, but remarkably they themselves fall on a striking linear trend. This observation, if more broadly true, has profound implications for materials sciences and understanding of solid‐state physics, as it implies that the compensation rule is itself compensated.
Paleointensity of the geomagnetic field in the Late Cretaceous and earliest Paleogene obtained from drill cores of the Louisville seamount trail
Authors: Yamazaki Toshitsugu , Yamamoto Yuhji
Published: May 2014

Information on the strength of the geomagnetic field is important for understanding the behavior of the geodynamo. Polarity reversal frequency increases toward the late Cenozoic since the end of the Cretaceous Normal Superchron. Accumulating reliable paleointensity data in this time interval is still desired for elucidating the possibility of a link between reversal frequency and paleointensity. We conducted a paleointensity study on 288 samples from four seamounts from ∼74 to ∼50 Ma in age that constitutes the Louisville seamount trail. Based on thermomagnetic curves and scanning electron microscopy, we first excluded 134 samples that showed evidence for low‐temperature oxidation. We then applied the Tsunakawa‐Shaw method with low‐temperature demagnetization and double heating after rejecting some samples that do not preserve stable primary remanence, and 52 successful results were obtained. An average virtual axial dipole moment (VADM) of 3.75 ± 1.52 (1022 Am2) was obtained at Site U1372 on Canopus seamount (∼74 Ma) based on 16 independent measurements. Sites U1373 and U1374 on Rigil seamount (∼70 Ma) yielded a mean of 3.79 ± 1.40 (n = 16), and Site U1376 on Burton seamount (∼65 Ma) yielded a mean of 3.70 ± 1.37 (n = 8). These VADMs are similar to the long‐term average of the last 200 Myr by Tauxe et al. (2013) and the mean of the last 5 Myr by Yamamoto and Tsunakawa (2005). The volcanic sequence drilled at Site U1372 probably belongs to Chron C33n of 5.59 Myr long, whereas others belong to shorter chrons. Our results support no discernible relationship between polarity length and paleointensity.
Global magnetodisk disturbances and energetic particle injections at Jupiter
Authors: Louarn Philippe , Paranicas Christopher P. , Kurth William S.
Published: May 2014

Measurements made by the Galileo Energetic Particles Detector and the plasma wave/radio instrument are analyzed to establish relationships between dynamic processes observed independently in the distant and the inner Jovian disk (at 80–120 Jovian radii (RJ) and 10–25 RJ, respectively). It is first shown that global magnetospheric disturbances identified from the radio emissions (the “energetic events” are well correlated with reconnection/reconfiguration events observed at the outer edge of the disk. Then, considering all Galileo perijoves, it is also demonstrated that the energetic events occurring as Galileo was at less than ~25 RJ are systematically associated with new injections of energetic particles seen from ~10 to 25 RJ. This demonstrates that major disturbances commonly affect the whole magnetodisk, from 10 to 80–120 RJ. Overall, their phenomenology involves simultaneous auroral activation, formation of new sources of radio emission (narrow‐band kilometric radiation) and particle injections in the Io torus, magnetic reconfigurations, and radial flow bursts in the distant disk, over time scale of a few hours.
MESSENGER observations of large dayside flux transfer events: Do they drive Mercury's substorm cycle?
Authors: Imber Suzanne M. , Slavin James A. , Boardsen Scott A. , Anderson Brian J. , Korth Haje , McNutt Ralph L. , Solomon Sean C.
Published: May 2014

The large‐scale dynamic behavior of Mercury's highly compressed magnetosphere is predominantly powered by magnetic reconnection, which transfers energy and momentum from the solar wind to the magnetosphere. The contribution of flux transfer events (FTEs) at the dayside magnetopause to the redistribution of magnetic flux in Mercury's magnetosphere is assessed with magnetic field data acquired in orbit about Mercury by the Magnetometer on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft. FTEs with core fields greater than the planetary field just inside the magnetopause are prevalent at Mercury. Fifty‐eight such large‐amplitude FTEs were identified during February and May 2012, when MESSENGER sampled the subsolar magnetosheath. The orientation of each FTE was determined by minimum variance analysis, and the magnetic flux content of each was estimated using a force‐free flux rope model. The average flux content of the FTEs was 0.06 MWb, and their durations imply a transient increase in the cross‐polar cap potential of ~25 kV. For a substorm timescale of 2–3 min, as indicated by magnetotail flux loading and unloading, the FTE repetition rate (10 s) and average flux content (assumed to be 0.03 MWb) imply that FTEs contribute at least ~30% of the flux transport required to drive the Mercury substorm cycle. At Earth, in contrast, FTEs are estimated to contribute less than 2% of the substorm flux transport. This result implies that whereas at Earth, at which steady‐state dayside reconnection is prevalent, multiple X‐line dayside reconnection and associated FTEs at Mercury are a dominant forcing for magnetospheric dynamics.
Managing flow, sediment, and hydropower regimes in the Sre Pok, Se San, and Se Kong Rivers of the Mekong basin
Authors: Wild Thomas B. , Loucks Daniel P.
Published: May 2014

The Lancang/Mekong River Basin is presently undergoing a period of rapid hydropower development. In its natural undeveloped state, the river transports about 160 million metric tons of sediment per year, maintaining the geomorphologic features of the basin, sustaining habitats, and transporting the nutrients that support ecosystem productivity. Despite the importance of sediment in the river, currently little attention is being paid to reservoir sediment trapping. This study is devoted to assessing the potential for managing sediment and its impact on energy production in the Se San, Sre Pok, and Se Kong tributaries of the Mekong River. These tributaries drain a set of adjacent watersheds that are important with respect to biodiversity and ecological productivity, and serve as a significant source of flow and sediment to the mainstream Mekong River. A daily sediment transport model is used to assess tradeoffs among energy production and sediment and flow regime alteration in multiple reservoir systems. This study finds that eventually about 40%–80% of the annual suspended sediment load may be trapped in reservoirs. Clearly, these reservoirs will affect the rivers' sediment regimes. However, even after 100 years of simulated sedimentation, reservoir storage capacities and hydropower production at most reservoir sites are not significantly reduced. This suggests that the strongest motivation for implementing measures to reduce trapped sediment is their impact not on hydropower production but on fish migration and survival and on sediment‐dependent ecosystems such as the Vietnam Delta and Cambodia's Tonle Sap Lake.
A self‐report measure of legal and administrative aggression within intimate relationships
Authors: Hines Denise A. , Douglas Emily M. , Berger Joshua L.
Published: May 2014

Although experts agree that intimate partner violence (IPV) is a multidimensional phenomenon comprised of both physical and non‐physical acts, there is no measure of legal and administrative (LA) forms of IPV. LA aggression is when one partner manipulates the legal and other administrative systems to the detriment of his/her partner. Our measure was developed using the qualitative literature on male IPV victims' experiences. We tested the reliability and validity of our LA aggression measure on two samples of men: 611 men who sustained IPV and sought help, and 1,601 men in a population‐based sample. Construct validity of the victimization scale was supported through factor analyses, correlations with other forms of IPV victimization, and comparisons of the rates of LA aggression between the two samples; reliability was established through Cronbach's alpha. Evidence for the validity and reliability of the perpetration scale was mixed and therefore needs further analyses and revisions before we can recommend its use in empirical work. There is initial support for the victimization scale as a valid and reliable measure of LA aggression victimization among men, but work is needed using women's victimization's experiences to establish reliability and validity of this measure for women. An LA aggression measure should be developed using LGBTQ victims' experiences, and for couples who are well into the divorce and child custody legal process. Legal personnel and practitioners should be educated on this form of IPV so that they can appropriately work with clients who have been victimized or perpetrate LA aggression. Aggr. Behav. 41:295–309, 2015. © 2014 Wiley Periodicals, Inc.
Inhibition of calcineurin combined with dasatinib has direct and indirect anti‐leukemia effects against BCR‐ABL1+ leukemia
Authors: Gardner Lori A. , Klawitter Jelena , Gregory Mark A. , Zaberezhnyy Vadym , Baturin Dmitry , Pollyea Daniel A. , Takebe Naoko , Christians Uwe , Gore Lia , DeGregori James , Porter Christopher C.
Published: May 2014

Treatment of BCR‐ABL1+ leukemia has been revolutionized with the development of tyrosine kinase inhibitors. However, patients with BCR‐ABL1+ acute lymphoblastic leukemia and subsets of patients with chronic myeloid leukemia are at high risk of relapse despite kinase inhibition therapy, necessitating novel treatment strategies. We previously reported synthetic lethality in BCR‐ABL1+ leukemia cells by blocking both calcineurin/NFAT signaling and BCR‐ABL1, independent of drug efflux inhibition by cyclosporine. Here, using RNA‐interference we confirm that calcineurin inhibition sensitizes BCR‐ABL1+ cells to tyrosine kinase inhibition in vitro. However, when we performed pharmacokinetic and pharmacodynamic studies of dasatinib and cyclosporine in mice, we found that co‐administration of cyclosporine increases peak concentrations and the area under the curve of dasatinib, which contributes to the enhanced disease control. We also report the clinical experience of two subjects in whom we observed more hematopoietic toxicity than expected while enrolled in a Phase Ib trial designed to assess the safety and tolerability of adding cyclosporine to dasatinib in humans. Thus, the anti‐leukemia benefit of co‐administration of cyclosporine and dasatinib is mechanistically pleiotropic, but may not be tolerable, at least as administered in this trial. These data highlight some of the challenges associated with combining targeted agents to treat leukemia. Am. J. Hematol. 89:896–903, 2014. © 2014 Wiley Periodicals, Inc.
Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the CooperativeStudy of SickleCellDisease
Authors: Meier Emily Riehm , Wright Elizabeth C. , Miller Jeffery L.
Published: May 2014

Prior analyses of the Cooperative Study of Sickle Cell Disease (CSSCD) newborn cohort identified elevated white blood cell (WBC) count, low baseline hemoglobin and dactylitis between the ages of 1 and 2 years as markers of severe disease. Reticulocytosis was also associated with severe disease. Here, we further analyzed data collected on enrolled CSSCD infants for the predictive value of those markers for stroke and death later in life. Three hundred fifty‐four CSSCD subjects were identified who had absolute reticulocyte counts (ARC) measured during infancy (2 to 6 months of age). Infants with higher ARC had significantly increased risk of stroke or death during childhood; lower hemoglobin levels also increased the risk but to a lesser degree than ARC. WBC levels and dactylitis were not predictive of death or stroke. These data suggest that reticulocytosis among asymptomatic infants with sickle cell anemia is associated with an increased risk of death or stroke during childhood. Am. J. Hematol. 89:904–906, 2014. © 2014 Wiley Periodicals, Inc.
A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia
Authors: Burke Michael J. , Lamba Jatinder K. , Pounds Stanley , Cao Xueyuan , Ghodke‐Puranik Yogita , Lindgren Bruce R. , Weigel Brenda J. , Verneris Michael R. , Miller Jeffrey S.
Published: May 2014

DNA hypermethylation and histone deacetylation are pathways of leukemia resistance. We investigated the tolerability and efficacy of decitabine and vorinostat plus chemotherapy in relapse/refractory acute lymphoblastic leukemia (ALL). Decitabine (15 mg/m2 iv) and vorinostat (230 mg/m2 PO div BID) were given days 1–4 followed by vincristine, prednisone, PEG‐asparaginase, and doxorubicin. Genome wide methylation profiles were performed in 8 matched patient bone marrow (BM) samples taken at day 0 and day 5 (postdecitabine). The median age was 16 (range, 3–54) years. All patients had a prior BM relapse, with five relapsing after allogeneic transplant. The most common nonhematological toxicities possibly related to decitabine or vorinostat were infection with neutropenia (grade 3; n = 4) and fever/neutropenia (grade 3, n = 4; grade 4, n = 1). Of the 13 eligible patients, four achieved complete remission without platelet recovery (CRp), two partial response (PR), one stable disease (SD), one progressive disease (PD), two deaths on study and three patients who did not have end of therapy disease evaluations for an overall response rate of 46.2% (CRp + PR). Following decitabine, significant genome‐wide hypo‐methylation was observed. Comparison of clinical responders with nonresponders identified methylation profiles of clinical and biological relevance. Decitabine and vorinostat followed by re‐Induction chemotherapy was tolerable and demonstrated clinical benefit in relapsed patients with ALL. Methylation differences were identified between responders and nonresponders indicating interpatient variation, which could impact clinical outcome. This study was registered at www.clinicaltrials.gov as NCT00882206. Am. J. Hematol. 89:889–895, 2014. © 2014 Wiley Periodicals, Inc.
A phase 2, randomized, double‐blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low‐ or intermediate‐1–risk myelodysplastic syndrome
Authors: Garcia‐Manero Guillermo , Gartenberg Gary , Steensma David P. , Schipperus Martin R. , Breems Dimitri A. , de Paz Raquel , Valcárcel David , Kranenburg Britte , Reddy Manjula , Komrokji Rami S.
Published: May 2014

Interleukin‐6 (IL‐6) may play an important role in the pathophysiology of anemia of inflammation associated with myelodysplastic syndrome (MDS). This double‐blind, placebo‐controlled, phase 2 study assessed the efficacy and safety of siltuximab, a chimeric anti–IL‐6 monoclonal antibody, in patients with low‐ and intermediate‐1–risk MDS who require transfusions for MDS anemia. Patients were randomized in a 2:1 ratio to siltuximab 15 mg kg−1 every 4 weeks + best supportive care (BSC) or placebo + BSC for 12 weeks. The primary endpoint was reduction in red blood cell (RBC) transfusions to treat MDS anemia, defined as ≥50% relative decrease and ≥2‐unit absolute decrease in RBC transfusions. Fifty and 26 patients were randomized to the siltuximab and placebo groups, respectively. The study did not meet its prespecified hypothesis, with six (12%) patients in the siltuximab group and one (3.8%) in the placebo group having reductions in RBC transfusions (P = 0.271). At the time of the planned futility analysis, the prespecified cutoff criteria were not met, and the study was terminated early due to lack of efficacy. No unexpected safety findings were observed. In conclusion, compared to placebo, treatment with siltuximab did not reduce RBC transfusions in transfusion‐dependent patients with low‐ and intermediate‐1–risk MDS. Future studies might explore siltuximab in patients with less iron overload and with elevated IL‐6 levels and/or using higher doses for MDS. Am. J. Hematol. 89:E156–E162, 2014. © 2014 Wiley Periodicals, Inc.
Brief communication: The size of the human frontal sinuses in adults presenting complete persistence of the metopic suture
Authors: Guerram Amine , Le Minor Jean‐Marie , Renger Stéphane , Bierry Guillaume
Published: May 2014

The notion of absence of the frontal sinuses in human individuals presenting a persistence of the metopic suture is considered as classical in many treatises of reference; however, precise studies are very rare and even controversial. The purpose of this study was thus to provide original data to confirm or refute this classical affirmation with the perspective of some original insights into biological significance of the frontal sinuses and the factors influencing their exceptional polymorphism. The material consisted of 143 dry skulls of adult individuals (European Homo sapiens), distributed in two groups: 80 skulls presenting a complete frontal closure with total disappearance of the metopic suture, and 63 skulls presenting a complete persistence of the metopic suture. Each skull was radiographed in oblique projection using the occipitomental view. A simple morphological quantification of the sinus size was defined with four categories: (1) aplasia, (2) hypoplasia, (3) medium size, (4) hyperplasia. Statistically significant difference in frontal sinusal size was found between both groups of skulls. Absent and small sinuses were considerably more frequent in skulls with persistence of the metopic suture (57.9 vs. 11.9%): small frontal sinuses (hypoplasia) were much more frequent (50.8 vs. 9.4%), although the frequency of absence of frontal sinuses (aplasia) was only slightly higher (7.1 vs. 2.5%). Am J Phys Anthropol 154:621–627, 2014. © 2014 Wiley Periodicals, Inc.
Polyhexamethylene guanidine hydrochloride shows bactericidal advantages over chlorhexidine digluconate against ESKAPE bacteria
Authors: Zhou Zhongxin , Wei Dafu , Lu Yanhua
Published: May 2014

More information regarding the bactericidal properties of polyhexamethylene guanidine hydrochloride (PHMG) against clinically important antibiotic‐resistant ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens needs to be provided for its uses in infection control. The bactericidal properties of PHMG and chlorhexidine digluconate (CHG) were compared based on their minimum inhibitory concentrations (MICs), minimum bactericidal concentrations, and time‐course–killing curves against clinically important antibiotic‐susceptible and antibiotic‐resistant ESKAPE pathogens. Results showed that PHMG exhibited significantly higher bactericidal activities against methicillin‐resistant Staphylococcus aureus, carbapenem‐resistant Klebsiella pneumoniae, and ceftazidime‐resistant Enterobacter spp. than CHG. A slight bactericidal advantage over CHG was obtained against vancomycin‐resistant Enterococcus faecium, ciprofloxacin‐ and levofloxacin‐resistant Acinetobacter spp., and multidrug‐resistant Pseudomonas aeruginosa. In previous reports, PHMG had higher antimicrobial activity against almost all tested Gram‐negative bacteria and several Gram‐positive bacteria than CHG using MIC test. These studies support the further development of covalently bound PHMG in sterile‐surface materials and the incorporation of PHMG in novel disinfectant formulas.
Enhancement of ginsenoside biosynthesis and secretion by Tween 80 in Panax ginseng hairy roots
Authors: Liang Yanlong , Wu Jianjun , Li Yao , Li Jian , Ouyang Yong , He Zhi , Zhao Shoujing
Published: May 2014

We evaluated the effect of Tween 80 permeabilization on ginsenoside secretion in Panax ginseng hairy roots. Tween 80 (1.2%, w/v) had no significant effect on hairy root vitality. After a 25‐day treatment with Tween 80, approximately 76% of the total ginsenosides was released into the surrounding medium. In the case of control, the ginsenosides secreted into the medium were negligible. Furthermore, when compared with control, the level of total ginsenosides was enhanced by approximately threefold under Tween treatment. Additionally, secretion of the typical ginsenoside monomers including Rb1, Rg1, and Re was analyzed, indicating that the most of them were released into the medium. Moreover, it was observed that dammarenediol synthase, a key enzyme involved in ginsenoside biosynthesis, was upregulated at both gene expression and enzyme activity levels. The expression of genes CYP716A47 and CYP716A53v2 encoding Cyt P450 enzymes catalyzing the formation of protopanaxadiol from dammarenediol and protopanaxatriol from protopanaxadiol, respectively, was slightly upregulated. These results clearly demonstrated that Tween 80 could act not only as an efficient permeabilizer to enhance ginsenoside secretion from the hairy roots, but also as an elicitor to promote the biosynthesis of ginsenoside.
CD and NMR conformational studies of a peptide encompassing the Mid Loop interface of Ship2–Sam
Authors: Mercurio Flavia A. , Scognamiglio Pasqualina L. , Di Natale Concetta , Marasco Daniela , Pellecchia Maurizio , Leone Marilisa
Published: May 2014

The lipid phosphatase Ship2 is a protein that intervenes in several diseases such as diabetes, cancer, neurodegeneration, and atherosclerosis. It is made up of a catalytic domain and several protein docking modules such as a C‐terminal Sam (Sterile alpha motif) domain. The Sam domain of Ship2 (Ship2–Sam) binds to the Sam domains of the EphA2 receptor (EphA2–Sam) and the PI3K effector protein Arap3 (Arap3–Sam). These heterotypic Sam–Sam interactions occur through formation of dimers presenting the canonical “Mid Loop/End Helix” binding mode. The central region of Ship2–Sam, spanning the C‐terminal end of α2, the α3 and α4 helices together with the α2α3 and α3α4 interhelical loops, forms the Mid Loop surface that is needed to bind partners Sam domains. A peptide encompassing most of the Ship2–Sam Mid Loop interface (Shiptide) capable of binding to both EphA2–Sam and Arap3–Sam, was previously identified. Here we investigated the conformational features of this peptide, through solution CD and NMR studies in different conditions. These studies reveal that the peptide is highly flexible in aqueous buffer, while it adopts a helical conformation in presence of 2,2,2‐trifluoroethanol. The discovered structural insights and in particular the identification of a helical motif, may lead to the design of more constrained and possibly cell permeable Shiptide analogs that could work as efficient antagonists of Ship2–Sam heterotypic interactions and embrace therapeutic applications. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 1088–1098, 2014.
Bacterial community structure and activity of sulfate reducing bacteria in a membrane aerated biofilm analyzed by microsensor and molecular techniques
Authors: Liu Hong , Tan Shuying , Sheng Zhiya , Liu Yang , Yu Tong
Published: May 2014

The activities and vertical spatial distribution of sulfate reducing bacteria (SRB) in an oxygen (O2)‐based membrane aerated biofilm (MAB) were investigated using microsensor (O2 and H2S) measurements and molecular techniques (polymerase chain reaction‐denaturing gradient gel electrophoresis [PCR‐DGGE] and fluorescence in situ hybridization [FISH]). The O2 concentration profile revealed that O2 penetrated from the bottom (substratum) of the gas permeable membrane, and was gradually consumed within the biofilm until it was completely depleted near the biofilm/bulk liquid interface, indicating oxic and anoxic zone in the MAB. The H2S concentration profile showed that H2S production was found in the upper 285 µm of the biofilm, indicating a high activity of SRB in this region. The results from DGGE of the PCR‐amplified dissimilatory sulfite reductase subunit B (dsrB) gene and FISH showed an uneven spatial distribution of SRB. The maximum SRB biomass was located in the upper biofilm. The information from the molecular analysis can be supplemented with that from microsensor measurements to better understand the microbial community and activity of SRB in the MAB. Biotechnol. Bioeng. 2014;111: 2155–2162. © 2014 Wiley Periodicals, Inc.
Construction of a yeast‐based signaling biosensor for human angiotensin II type 1 receptor via functional coupling between Asn295‐mutated receptor and Gpa1/Gi3 chimeric Gα
Authors: Nakamura Yasuyuki , Ishii Jun , Kondo Akihiko
Published: May 2014

Angiotensin II (Ang II) type 1 receptor (AGTR1) is a G‐protein‐coupled receptor (GPCR). Its natural ligand, Ang II, is an important effector molecule controlling blood pressure and volume in the cardiovascular system, and is consequently involved in various diseases such as hypertension and heart failure. Thus, the signaling mediator, AGTR1, is a significant molecular target in medicinal and therapeutic fields. Yeast is a useful organism for sensing GPCR signaling because it provides a simplified version of the complicated machinery used by mammalian cells for signal transduction. Although yeast cells can successfully transmit a signal through a variety of human GPCRs expressed in the cell membrane, there have been no reports of the functional activation of AGTR1‐mediated signaling in yeast cells. In the present study, we introduced a single mutation into human AGTR1 and used yeast‐human chimeric Gα to exert the functional activation of AGTR1 in yeast cells. The engineered yeast cells expressing AGTR1 mutated at Asn295 and the chimeric Gα successfully transmitted the signal inside the yeast cells in response to Ang II peptide and its analogs (Ang III and Ang IV peptides) added to the assay medium. Further, we demonstrated that the autocrine Ang II peptide and its analog, produced and secreted by the engineered yeast cells, could by themselves promote AGTR1‐mediated signaling. This means that screening for agonistic peptides with various sequences from a self‐produced genetic library would be a viable strategy. Thus, the constructed yeast biosensor, integrating an Asn295‐mutated AGTR1 receptor, will be valuable in the design of drugs to treat AGTR1‐related diseases. Biotechnol. Bioeng. 2014;111: 2220–2228. © 2014 Wiley Periodicals, Inc.
Magnetostrictive particle based biosensors for in situ and real‐time detection of pathogens in water
Authors: Zhang Kewei , Fu Liling , Zhang Lin , Cheng Z.‐Y. , Huang Tung‐Shi
Published: May 2014

Biosensors for in situ detection of pathogenic bacteria in liquid are developed using magnetostrictive particles (MSP) as the sensor platform. The sensing elements used are phage E2 against Salmonella typhimurium, monoclonal antibody against Listeria monocytogenes, polyclonal antibody against Escherichia coli, and polyclonal antibody against Staphylococcus aureus, respectively. These biosensors were characterized in cultures with different populations ranging from 5 × 101 to 5 × 108 cfu/mL. It is found that the MSP‐based biosensors work well in water and have a rapid response with a response time in minutes, which makes the MSP‐based sensors suitable for in situ and real‐time detection of pathogenic bacteria in liquid. The experimental results show that all MSP‐phage and MSP‐antibody biosensors in size of 1.0 mm × 0.3 mm × 15 µm exhibit a detection limit better than 100 cfu/mL. Based on the Hill plot, it is concluded that each bacterial cell is bound onto the sensor surface through about four‐to‐five sites. When the cultures with low population (<106 cfu/mL) are tested, both MSP‐phage and MSP‐antibody sensors exhibit the similar response. However, the phage‐MSP sensors exhibit a higher capability in the capture of target bacterial cell. Biotechnol. Bioeng. 2014;111: 2229–2238. © 2014 Wiley Periodicals, Inc.
Specific photosynthetic rate enhancement by cyanobacteria coated onto paper enables engineering of highly reactive cellular biocomposite “leaves”
Authors: Bernal Oscar I. , Mooney Charles B. , Flickinger Michael C.
Published: May 2014

We describe a latex wet coalescence extrusive coating method that produces up to 10‐fold specific photosynthetic rate enhancements by nitrate‐limited non‐growing cyanobacteria deposited onto paper, hydrated and placed in the gas‐phase of small tube photobioreactors. These plant leaf‐like biocomposites were used to study the tolerance of cyanobacteria strains to illumination and temperature using a solar simulator. We report sustained CO2 absorption and O2 production for 500 h by hydrated gas‐phase paper coatings of non‐growing Synechococcus PCC7002, Synechocystis PCC6803, Synechocystis PCC6308, and Anabaena PCC7120. Nitrate‐starved cyanobacteria immobilized on the paper surface by the latex binder did not grow out of the coatings into the bulk liquid. The average CO2 consumption rate in Synechococcus coatings is 5.67 mmol m−2 h−1 which is remarkably close to the rate reported in the literature for Arabidopsis thaliana leaves under similar experimental conditions (18 mmol m−2 h−1). We observed average ratios of oxygen production to carbon dioxide consumption (photosynthetic quotient, PQ) between 1.3 and 1.4, which may indicate a strong dependence on nitrate assimilation during growth and was used to develop a non‐growth media formulation for intrinsic kinetics studies. Photosynthetic intensification factors (PIF) (O2 production by nitrate‐limited cyanobacteria in latex coatings/O2 produced by nitrate‐limited cell suspensions) in cyanobacteria biocomposites prepared from wet cell pellets concentrated 100‐ to 300‐fold show 7–10 times higher specific reactivity compared to cells in suspension under identical nitrate‐limited non‐growth conditions. This is the first report of changes of cyanobacteria tolerance to temperature and light intensities after deposition as a thin coating on a porous matrix, which has important implications for gas‐phase photobioreactor design using porous composite materials. Cryo‐fracture SEM and confocal microscopy images of cell coating distribution on the paper biocomposite suggest that the spatial arrangement of the cells in the coating can affect photoreactivity. This technique could be used to fabricate very stable, multi‐organism composite coatings on flexible microfluidic devices in the gas‐phase capable of harvesting light in a broader range of wavelengths, to optimize thermotolerant, desiccation tolerant, or halotolerant cyanobacteria that produce O2 with secretion of liquid‐fuel precursors synthesized from CO2. Biotechnol. Bioeng. 2014;111: 1993–2008. © 2014 Wiley Periodicals, Inc.