bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalized Estimating Equations
Authors: Hardin James W. , Hilbe Joseph M.
Published: January 2014

Correlated datasets develop when multiple observations are collected from a sampling unit (e.g., repeated measures of a bank over time, or hormone levels in a breast cancer patient over time), or from clustered data where observations are grouped based on a shared characteristic (e.g., observations on different banks grouped by zip code, or on cancer patients from a specific clinic). The generalized linear model framework for independent data is extended to model correlated data via the introduction of second‐order variance components directly into the independent data model's estimating equation. This generalization of the estimating equation from the independence model is thus referred to as a Generalized Estimating Equation (GEE). This article discusses the foundation of GEEs as well as how user‐specified correlation structures are accommodated in the model‐building process. This article also discusses the relationship and similarity to the underlying generalized linear model framework and we point out alternative approaches to GEEs for modeling correlated data such as fixed‐effects models and random‐effects models.
Group‐Randomized Trials
Authors: Murray David M.
Published: January 2014

The purpose of this article is to put group‐randomized trials (GRTs) in context in terms of other kinds of designs and in terms of the terminology used in other fields, to summarize their development in public health, to characterize the range of public health research areas that now employ GRTs, to characterize the state of practice with regard to the design and analysis of GRTs, to consider their future in public health research, and to review the steps required to plan a new GRT.
Proportional Odds Model
Authors: Liu Ivy , Mukherjee Bhramar
Published: January 2014

Outcomes recorded on an ordinal scale, such as severity of migraine, stages of progression of disease, or degree of relief caused by treatment, occur commonly in clinical trials. Questionnaire data, which are often collected at each visit to gauge patient condition, routinely contain responses on an ordinal scale. Naïve dichotomization of the full ordinal scale leads to loss of information and efficiency while analyzing such outcomes. The proportional odds model is a popular choice for analyzing such ordinal outcomes. The current article provides a concise introduction to the proportional odds model and proceeds to review some more recent work related to this model. Specifically, we discuss the problem of analyzing stratified ordinal data in which observations from the same strata are correlated. Such correlated ordinal data may develop in multicenter clinical trials or with ordinal responses measured repeatedly on the same subject in longitudinal studies. Certain computing tools for fitting such models are discussed.
Nonparametric Methods
Authors: Wolfe Douglas A.
Published: January 2014

The motivation behind distribution‐free hypothesis tests and confidence intervals based on signs and ranks is discussed and standard text references are provided. Distribution‐free test and confidence interval procedures for the one‐sample, two‐sample, one‐way analysis of variance, two‐way analysis of variance, and independence settings are presented. Point estimation techniques, including Hodges–Lehmann estimators and contrast estimation, and multiple comparisons procedures are described. Basic references for censored data approaches and bootstrapping are provided.
ASCOTTrial
Authors: Mehlsen Jesper
Published: January 2014

The Anglo Scandinavian Cardiac Outcomes Trial (ASCOT) had two main objectives. The first objective was to determine and compare the effects of an amlodipine‐based therapy with an atenolol‐based therapy in hypertensive patients with mild‐to‐moderate risk of developing cardiovascular events (ASCOT‐BPLA). The second objective was in those patients with a serum cholesterol level at or below average to evaluate the possible beneficial effects on cardiovascular events of a statin compared with placebo (ASCOT‐LLA). ASCOT‐LLA was terminated prematurely after a mean observational period of 3.3 years because of a highly significant reduction in the primary endpoint of CHD events compared with placebo. ASCOT‐BPLA was also terminated prematurely after a mean observational period of 5.5 years because of significantly higher all cause mortality in the atenolol‐based treatment arm compared with the amlodipine‐based arm.
AIDSClinical Trials Group (ACTG)
Authors: Andersen Janet W.
Published: January 2014

The AIDS Clinical Trials Group (ACTG) is the largest Network conducting therapeutic clinical trials in AIDS and HIV, with active clinical sites in the United States, South America, Haiti, Africa, India, and Thailand. The ultimate goal of the ACTG is to identify drugs and other treatment modalities that will result in the successful control of HIV in infected persons.
DNA
Bank
Authors: Sivakumaran Theru A , Iyengar Sudha K
Published: January 2014

Most diseases are multifactorial and are caused by a combination of genetic and environmental factors. Similarly, the way a person responds to a drug is also a complex trait that is influenced by many different genes. Paradigms to identify causative genetic variants responsible for disease or response to drugs are well described in the literature, and the following essential elements are required for successful completion of such studies: (
1
) rapid detection of genetic variation; (
2
) large number of samples of high quality with well‐characterized clinical data from participants, which includes longitudinal follow‐up for effect of treatment; (
3
) advanced informatics for storage and retrieval of samples and data; and (
4
) establishment of correlation between clinical and genetic data through modern statistical techniques. Although the basic conventions for sample collection in gene mapping were already established, it was only after completion of Human Genome Project and the initiation of the International HapMap Project that the need for large databases of well‐phenotyped study participants collected under unified protocols with DNA available was expressed. These endeavors resulted in the establishment of national and international DNA banks aimed initially at mapping specific disease entities, but later encompassing more global undertakings. Establishment of these DNA biobanks has not been without ethical, legal, and personal controversies, although their value to the biomedical research community is indisputable. The overall outcome of these initiatives is that the promise of personalized medicine is nearby, particularly for identification of the genetic variations responsible for drug response. We anticipate that clinical trials could perform genetic prescreening to exclude people who are unresponsive to treatment, which reduces side effects and increases the effectiveness of the drug for particular subgroups. This model is already being implemented for the P450 class of drugs, with the hope of more to come.
Benefit/Risk Assessment in Prevention Trials
Authors: Costantino Joseph P.
Published: January 2014

Benefit/risk assessment (B/RA) is a mathematical procedure to estimate the probability of detrimental outcomes, beneficial outcomes and the net‐effect anticipated from exposure to a given agent or procedure. B/RAs of health‐related outcomes are used for public health planning, decision‐making regarding health care financing, and therapeutic decision‐making in clinical practice. Information obtained from B/RAs based on findings from controlled clinical trials, particularly those with double‐masking of treatment, are most informative for health care planning and decision making because such information is less likely to be bias than is information obtained from observational studies. Thus, B/RAs in prevention trials are an excellent source of information to use as the basis for health care planning and decision‐making. Applications of R/BA in prevention trials are performed as supplements for planning, monitoring and analyzing the trial. These applications can be categorized into three types of assessments. This article provides a description of the three types of assessment performed in prevention trials, defines the statistical algorithms used for each type of assessment and discusses several key methodological and practical issues involve with the application of B/RA to health‐related outcomes.
Assessment of Health‐Related Quality of Life
Authors: Weng C. S. Wayne
Published: January 2014

This article is intended to provide an overview of assessment of HRQOL in clinical trials. For more specific details on a particular topic mentioned in this article, the readers should consult the cited references. The development of a new HRQOL questionnaire and its translation into various languages are separate topics and are not covered in this article.
The counterintuitive effect of summer‐to‐fall mixed layer deepening on eukaryotic new production in the Sargasso Sea
Authors: Fawcett Sarah E. , Lomas Michael W. , Ward Bess B. , Sigman Daniel M.
Published: January 2014

The Sargasso Sea is characterized by strong summertime stratification that is thought to drive oligotrophy, but export production is surprisingly similar to that of high‐latitude regions with ample major nutrient supply. Here we use the summer‐to‐fall progression in the northwestern Sargasso Sea to investigate the relationship between upper ocean stratification and phytoplankton nitrogen (N) uptake. Euphotic zone particles collected in July, October, and December were sorted by flow cytometry, and the 15N/14N of separated prokaryotic and eukaryotic phytoplankton was analyzed. The 15N/14N of Prochlorococcus and Synechococcus was always low, indicating uniform reliance on recycled N. In July and in two fall profiles, the 15N/14N of eukaryotic phytoplankton was high, reflecting consumption of subsurface nitrate. In three other fall profiles, eukaryotic 15N/14N was similar to prokaryote 15N/14N, suggesting a shift toward more complete reliance on recycled N. The progressive deepening of the mixed layer from summer to fall, although reducing the surface‐to‐deep density contrast, increases the density difference of the euphotic zone as a whole from underlying nutrient‐rich waters, which may play a role in the observed decline in euphotic zone nitrate supply into the fall. The apparent summertime nitrate supply to the euphotic zone, when the mixed layer is shallowest, may help to explain the surprisingly high export production of the subtropical and tropical ocean.
Optical measurements of small deeply penetrating bubble populations generated by breaking waves in the Southern Ocean
Authors: Randolph Kaylan , Dierssen Heidi M. , Twardowski Michael , Cifuentes‐Lorenzen Alejandro , Zappa Christopher J.
Published: January 2014

Bubble size distributions ranging from 0.5 to 125 μm radius were measured optically during high winds of 13 m s−1 and large‐scale wave breaking as part of the Southern Ocean Gas Exchange Experiment. Very small bubbles with radii less than 60 µm were measured at 6–9 m depth using optical measurements of the near‐forward volume scattering function and critical scattering angle for bubbles (∼80°). The bubble size distributions generally followed a power law distribution with mean slope values ranging from 3.6 to 4.6. The steeper slopes measured here were consistent with what would be expected near the base of the bubble plume. Bubbles, likely stabilized with organic coatings, were present for time periods on the order of 10–100 s at depths of 6–9 m. Here, relatively young seas, with an inverse wave age of approximately 0.88 and shorter characteristic wave scales, produced lower bubble concentrations, shallower bubble penetration depths, and steep bubble size distribution slopes. Conversely, older seas, with an inverse wave age of 0.70 and longer characteristic wave scales, produced relatively higher bubble concentrations penetrating to 15 m depth, larger bubble sizes, and shallower bubble size distribution slopes. When extrapolated to 4 m depth using a previously published bubble size distribution, our estimates suggest that the deeply penetrating small bubbles measured in the Southern Ocean supplied ∼36% of the total void fraction and likely contributed to the transfer and supersaturation of low‐solubility gases.
Deep water circulation in the Luzon Strait
Authors: Zhao Wei , Zhou Chun , Tian Jiwei , Yang Qingxuan , Wang Bin , Xie Lingling , Qu Tangdong
Published: January 2014

Deep water circulation in the Luzon Strait, which connects the Pacific deep circulation with the South China Sea throughflow, is investigated using a set of oceanographic observations combined with results from three numerical experiments. Both the in situ observations and the model show a deep water overflow in the Luzon Strait. Their results suggest that the deep Pacific water first flows into the Luzon Strait through the Bashi Channel (1.2 Sv, 1 Sv = 1 × 106 m3 s−1) and the Taltung Canyon (0.4 Sv), then turns southward along the Luzon Trough, and finally enters the South China Sea primarily through two gaps in the Heng‐Chun Ridge. Overall, the mean transport of the Luzon Strait overflow is about 1.5 Sv. Results from numerical experiments suggest that strong diapycnal mixing in the South China Sea and Luzon Strait, which sustains the baroclinic pressure gradient across the Luzon Strait, is the primary driving mechanism of the deep circulation in the Luzon Strait.
Multihop relaying for broadband wireless access systems at 800 and 3500 MHz in rural areas
Authors: Chee Kin Lien , Feng Wei , Kürner Thomas
Published: January 2014

This paper addresses the coverage enhancement for broadband wireless access (BWA) at 800 and 3500 MHz in a rural scenario in north Germany using multi‐hop relay concepts. The investigation is divided into two phases: In phase I, the coverage of a single BWA system in a rural area is predicted and verified with measurement data. In phase II, the coverage from the BWA system is analyzed and enhanced through the deployment of relay stations. The number of relay stations required for each carrier frequency is determined, and the positions of the relay stations are identified via three different relay placement algorithms, namely path‐loss‐based, distance‐based, and hybrid algorithms. At 800 MHz, the path‐loss‐based algorithm requires seven relay stations to achieve an overall coverage of 95%. The hybrid and distance‐based algorithms require 11 and 14 relay stations, respectively, to achieve the same coverage. At 3500 MHz, path‐loss based and hybrid algorithms require 19 and 16 relay stations, respectively, to achieve the same coverage. The distance‐based requires 20 relay stations to achieve an overall coverage of 82%. Further increase of relay stations has led to higher interference. Lastly, the transmit power of the relay station is optimized via an intelligent power allocation scheme. The results show that 20% of the total transmit powers from 14 relay stations can be saved at 800 MHz whereas 18% of the total transmit powers from the 20 relay stations can be saved at 3500 MHz.
New ice core record shows climate variability in West Antarctica
Authors: Balcerak Ernie
Published: January 2014

A 308‐year ice core record provides new data on climate variability in coastal West Antarctica and shows that a clear warming trend has occurred in recent decades. To study climate over the past 3 centuries, Thomas et al. analyzed stable isotopes in the ice core, which provide a record of past temperatures. They observed that climate variability in coastal West Antarctica is strongly driven by sea surface temperatures and atmospheric pressure in the tropical Pacific.
Laboratory experiments examine earthquake precursors
Authors: Balcerak Ernie
Published: January 2014

Although it is not possible to predict when an earthquake will occur, many earthquakes have been found to have had some precursor activity. To study precursors of stick‐slip behavior, Johnson et al. conducted laboratory experiments on a sheared granular material under normal stress ranging from 2 to 8 megapascals as an analog for a fault under tectonic stress. They found that acoustic emissions and microslips are a precursor to larger movements. Very similar results were obtained in a discrete element simulation of sheared beads. These types of experiments could help scientists better understand when earthquakes are more likely to occur. As shown by a number of researchers, very similar activity preceding faulting can occur in the Earth.
Single‐Molecule Spectroscopy of Motor Proteins
Authors: Prevo Bram , Acar Seyda , Kruijssen Dennis L.H. , Peterman Erwin J.G.
Published: January 2014

Single‐molecule fluorescence spectroscopy has become a crucial tool to study the behavior of biomolecules and their roles in complex biological processes. Single‐molecule methods have in particular contributed to our understanding of the mechanism of force generation and motility of motor proteins. Motor proteins are enzymes that convert the chemical free energy obtained from the hydrolysis of adenosine triphosphate (ATP) into mechanical work in order to drive processes such as muscle contraction and intracellular transport. Here, we review how single‐molecule fluorescence spectroscopy can be applied to motor proteins of the kinesin, myosin, and dynein superfamilies and how such studies have advanced our knowledge of the molecular basis of motor protein action.
Adhesion and Surface Interactions of a Self‐Healing Polymer with Multiple Hydrogen‐Bonding Groups
Authors: Faghihnejad Ali , Feldman Kathleen E. , Yu Jing , Tirrell Matthew V. , Israelachvili Jacob N. , Hawker Craig J. , Kramer Edward J. , Zeng Hongbo
Published: January 2014

The surface properties and self‐adhesion mechanism of self‐healing poly(butyl acrylate) (PBA) copolymers containing comonomers with 2‐ureido‐4[1H]‐pyrimidinone quadruple hydrogen bonding groups (UPy) are investigated using a surface forces apparatus (SFA) coupled with a top‐view optical microscope. The surface energies of PBA–UPy4.0 and PBA–UPy7.2 (with mole percentages of UPy 4.0% and 7.2%, respectively) are estimated to be 45–56 mJ m−2 under dry condition by contact angle measurements using a three probe liquid method and also by contact and adhesion mechanics tests, as compared to the reported literature value of 31–34 mJ m−2 for PBA, an increase that is attributed to the strong UPy–UPy H‐bonding interactions. The adhesion strengths of PBA–UPy polymers depend on the UPy content, contact time, temperature and humidity level. Fractured PBA–UPy films can fully recover their self‐adhesion strength to 40, 81, and 100% in 10 s, 3 h, and 50 h, respectively, under almost zero external load. The fracture patterns (i.e., viscous fingers and highly “self‐organized” parallel stripe patterns) have implications for fabricating patterned surfaces in materials science and nanotechnology. These results provide new insights into the fundamental understanding of adhesive mechanisms of multiple hydrogen‐bonding polymers and development of novel self‐healing and stimuli‐responsive materials.
Estimation of breakthrough time for water coning in fractured systems: Experimental study and connectionist modeling
Authors: Zendehboudi Sohrab , Elkamel Ali , Chatzis Ioannis , Ahmadi Mohammad Ali , Bahadori Alireza , Lohi Ali
Published: January 2014

Water coning in petroleum reservoirs leads to lower well productivity and higher operational costs. Adequate knowledge of coning phenomena and breakthrough time is essential to overcome this issue. A series of experiments using fractured porous media models were conducted to investigate the effects of production process and pore structure characteristics on water coning. In addition, a hybrid artificial neural network (ANN) with particle swarm optimization (PSO) algorithm was applied to predict breakthrough time of water coning as a function of production rate and physical model properties. Data from the literature combined with experimental data generated in this study were used to develop and verify the ANN‐PSO model. A good correlation was found between the predicted and real data sets having an absolute maximum error percentage less than 9%. The developed ANN‐PSO model is able to estimate breakthrough time and critical production rate with higher accuracy compared to the conventional or back propagation (BP) ANN (ANN‐BP) and common correlations. The presence of vertical fractures was found to accelerate considerably the water coning phenomena during oil production. Results of this study using combined data suggest the potential application of ANN‐PSO in predicting the water breakthrough time and critical production rate that are critical in designing and evaluating production strategies for naturally fractured reservoirs. © 2014 American Institute of Chemical EngineersAIChE J, 60: 1905–1919, 2014
Critical seed loading from nucleation kinetics
Authors: Tseng Yu‐Ti , Ward Jeffrey D.
Published: January 2014

A method is presented for preparing critical seed loading diagrams for nonaggregating systems knowing only the nucleation kinetics. This is advantageous because it is much less time‐consuming than developing and solving a complete batch process model including solubility expressions and growth rate kinetics. Furthermore, there are many more reports available in the literature of nucleation kinetics alone than there are of complete batch crystallization process models, because expressions for the nucleation rate as a function of crystal growth rate can be rapidly determined from mixed‐suspension, mixed‐product‐removal (MSMPR) data without measuring the supersaturation. The results for 43 systems show that there is a great deal of variability in the critical seed loading, and a single correlation is inadequate to describe the relationship between critical seed loading and seed size. For a seed size of 10 µ, seed loading can effectively suppress nucleation in 92% of cases, while for seeds of size 50, 100, and 200 µ, seed loading can suppress nucleation in 74, 61, and 39% of cases, respectively. © 2014 American Institute of Chemical Engineers AIChE J, 60: 1645–1653, 2014
A family study of trichotillomania and chronic hair pulling
Authors: Keuthen Nancy J. , Altenburger Erin M. , Pauls David
Published: January 2014

Little is known about the etiology of hair pulling (HP) and its relationship to other obsessive compulsive (OC) spectrum disorders. In a large‐sample family study, we examined the familial aggregation of HP and co‐transmission of obsessive compulsive disorder (OCD) and skin picking (SP). Our sample consisted of 110 proband cases with HP and 48 controls without HP, plus 128 first‐degree case relatives and 50 first‐degree control relatives. Case versus control relatives had higher recurrence risk estimates for both HP and OCD but not SP. The finding that HP is familial is consistent with the only existing twin study. Additional analyses suggest that there may be a familial subtype of HP with comorbid OCD. Those adult proband cases with HP + OCD had more anxiety and depression than cases without OCD. Probands with HP + OCD also had earlier onset of OCD. Identification of an HP subtype with comorbid OCD may have significant theoretical and treatment implications. The data did not provide evidence for an etiologic relationship between HP and SP. Replication of these findings in future studies with larger cohorts of case and control relatives is warranted. © 2014 Wiley Periodicals, Inc.
Angioedema of the upper aerodigestive tract: risk factors associated with airway intervention and management algorithm
Authors: Brook Christopher D. , Devaiah Anand K. , Davis Elizabeth M.
Published: January 2014

Background

Angioedema of the upper aerodigestive tract can lead to significant airway obstruction. To date no articles have delineated risk factors for progression after initial evaluation.

Methods

This article presents the results of a retrospective study of patients with angioedema at a single institution. Patients included were consecutive otolaryngology consultations for angioedema in the emergency department (ED) from 1999 to 2003. All patients were evaluated by an otolaryngologist and underwent fiber‐optic laryngoscopy, which was repeated serially depending on findings. Data was collected on demographics, comorbidities, intubation, disposition, and progression of angioedema.

Results

A total of 177 patients were included in the study: 32 (18%) patients required intubation; 25 (14%) on initial presentation and 7 (4%) who progressed from an initially stable airway to requiring intervention after reevaluation. Analysis of variance (ANOVA) demonstrated a statistically significant variance between location of edema and rate of intubation, with higher rates in the pharynx and larynx vs the lip and face. Patients who required intubation after progression between serial evaluations were statistically more likely to have edema that involved deeper portions of the aerodigestive tract. Patients who required intubation were statistically more likely to be older (average age 61.8 vs 55.1 years, p = 0.03).

Conclusion

In this large series of patients managed for aerodigestive angioedema we demonstrate risk factors associated with airway intervention, and risk factors associated with clinical progression on serial examination to airway intervention. In addition, we demonstrate a successful management algorithm for patients with aerodigestive angioedema.
Impact of vitamin D deficiency upon clinical presentation in nasal polyposis
Authors: Schlosser Rodney J. , Soler Zachary M. , Schmedes Gregg W. , Storck Kristina , Mulligan Jennifer K.
Published: January 2014

Background

The objective of this work was to determine if specific chronic rhinosinusitis with nasal polyps (CRSwNP) populations are at risk for vitamin D3 (VD3) deficiency and if VD3 levels correlate with radiographic measures of disease severity or eosinophilia.

Methods

This study was a retrospective review of an academic rhinology practice. CRSwNP patients who had VD3 levels and CT scan within 6 months of each other were included. CT scans were graded using Lund‐Mackay scoring (LMS) and peripheral eosinophil counts were measured. Demographic data including race, gender, age, body mass index, atopic status, and presence of asthma were collected. CRSwNP was subdivided into allergic fungal rhinosinusitis (AFRS), aspirin‐exacerbated respiratory disease (AERD), and other CRSwNP. Multivariate analysis was performed to examine correlations and control for confounding factors.

Results

Insufficient VD3 levels were found in 55% of all CRSwNP patients. VD3 correlated with African American race because nearly 80% of all African Americans had insufficient VD3 levels. Lower VD3 levels also correlated with more severe mucosal disease on CT scans as measured by LMS. There was no correlation between VD3 levels and age, gender, body mass index, atopy, asthma, or CRSwNP subtype.

Conclusion

VD3 insufficiency/deficiency is common in CRSwNP patients, especially those of African American race. Lower levels of VD3 are associated with worse LMS on CT. The role of VD3 in CRSwNP warrants further investigation.
Removal of Heavy Metals from Landfill Leachate Using Municipal Solid Waste Incineration Fly Ash as Adsorbent
Authors: Xue Qiang , Li Jiang‐Shan , Wang Ping , Liu Lei , Li Zhen‐Ze
Published: January 2014

To study the adsorption effect of municipal solid waste incineration (MSWI) fly ash on removal of heavy metals from landfill leachate, batch tests were performed to study the effects of MSWI fly ash dosage, pH of leachate, and reaction time on adsorption. The adsorption mechanism of MSWI fly ash to heavy metals was analyzed through scanning electron microscope and X‐ray diffraction tests. With fly ash dosage of 10 g/L, leachate pH 9, and reaction time of 60 min, the removal rate of Zn, Pb, Cr, Cd, and Cu in the leachate reached 39.42, 59.24, 28.14, 55.37, and 32.82%, respectively. The pseudo first‐order kinetic equation could well fit the adsorption kinetic process. The adsorption mechanisms of MSWI fly ash to heavy metals in the leachate mainly included ion exchange adsorption, electrostatic adsorption, and chemical fixation.
Mutagenetic and electron microscopy analysis of actin filament severing by Cordon‐Bleu, a WH2 domain protein
Authors: Jiao Yue , Walker Matt , Trinick John , Pernier Julien , Montaville Pierre , Carlier Marie‐France
Published: January 2014

Cordon‐Bleu (Cobl) is a regulator of actin dynamics in neural development and ciliogenesis. Its function is associated with three adjacent actin binding WASP Homology 2 (WH2) domains. We showed that these WH2 repeats confer multifunctional regulation of actin dynamics, which makes Cobl a « dynamizer » of actin assembly, inducing fast turnover of actin filaments and oscillatory polymerization regime via nucleation, severing, and rapid depolymerization activities. Cobl is the most efficient severer of actin filaments characterized so far. To understand which primary sequence elements determine the filament severing activity of the WH2 repeats, here we combine a mutagenetic/domain swapping approach of the minimal fully active Cobl‐KAB construct, which comprises the lysine rich region K preceding the two first WH2 domains A and B. The mutated Cobl constructs display variable loss of the original filament nucleating activities of native Cobl‐KAB, without any strict correlation with a loss in actin binding, which emphasizes the functional importance of the electrostatic environment of WH2 domains. Filament severing displayed the greatest stringency and was abolished in all mutated forms of Cobl‐KAB. Filament severing and re‐annealing by Cobl‐KAB, which is key in its rapid remodeling of a population of actin filaments, and most likely responsible for its function in ciliogenesis, was analyzed by electron microscopy in comparison with Spire and ADF. © 2014 Wiley Periodicals, Inc.
Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer
Authors: Fernandes Priscilla H. , Saam Jennifer , Peterson Jenny , Hughes Elisha , Kaldate Rajesh , Cummings Shelly , Theisen Aaron , Chen Sonia , Trost Jeffrey , Roa Benjamin B.
Published: January 2014

BACKGROUND

This study sought to determine the prevalence of PALB2 mutations in a cohort referred for diagnostic testing for hereditary breast cancer.

METHODS

Sanger sequencing was used to analyze the entire coding region and flanking introns of PALB2 in anonymized DNA samples from 1479 patients. Samples were stratified into a “high‐risk” group, 955 samples from individuals predicted to have a high probability of carrying a mutation in BRCA1 or BRCA2 based on their personal and family history, and a “lower‐risk” group consisting of 524 samples from patients with breast cancer, but fewer risk factors for being a BRCA1 or BRCA2 mutation carrier. All patients were known to be negative for deleterious sequence mutations and large rearrangements in BRCA1 and BRCA2.

RESULTS

We identified 12 disease‐associated PALB2 mutations among the 1479 patients (0.8%). The PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice‐site mutation. The mutation prevalence for the high‐risk population was 1.05% (95% CI = 0.5‐1.92), whereas that for the lower‐risk population was 0.38% (95% CI = 0.05‐1.37). We identified 59 PALB2 variants of uncertain significance (VUS) among 57 of the 1479 patients (3.9%).

CONCLUSIONS

These results suggest that PALB2 mutations occur at a frequency of ∼1% in patients with hereditary breast cancer. Cancer 2014;120:963–967. © 2013 American Cancer Society.
EWS‐FLI‐1 regulates the neuronal repressor gene REST, which controls Ewing sarcoma growth and vascular morphology
Authors: Zhou Zhichao , Yu Ling , Kleinerman Eugenie S.
Published: January 2014

BACKGROUND

RE1‐silencing transcription factor (REST), a neuronal repressor gene, regulates neuronal stem cell differentiation. Ewing sarcoma may originate from neural crest cells. In the current study, the authors investigated whether REST plays a role in the growth of this tumor.

METHODS

REST expression was determined by Western blot analysis and reverse transcription‐polymerase chain reaction in 3 human Ewing sarcoma cell lines and 7 patient tumor samples. The role of REST in tumor growth and tumor vascular morphology was determined using a Ewing sarcoma xenograft model. Immunofluorescence staining, Hypoxyprobe, and terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) assays were performed to investigate the impact of REST on pericyte marker expression, hypoxia, and apoptosis in vivo.

RESULTS

High levels of REST were expressed in all 3 human Ewing sarcoma cell lines and in 6 of the 7 patient tumor samples. Overexpression of EWS‐FLI‐1 in human mesenchymal stem cells and human neural progenitor cells was found to increase REST expression. Inhibition of EWS‐FLI‐1 using small interfering RNA decreased REST expression in human Ewing sarcoma cells. Inhibition of REST did not affect EWS‐FLI‐1, but significantly suppressed tumor growth in vivo, reduced the tumor vessel pericyte markers α‐ smooth muscle actin (SMA) and desmin, increased hypoxia and apoptosis in tumor tissues, and decreased the expression of delta‐like ligand 4 (DLL4) and Hes1.

CONCLUSIONS

Inhibition of REST suppressed tumor growth, inhibited pericyte marker expression, and increased tumor hypoxia and apoptosis. Because tumor vessel function has been linked to tumor growth and metastases, REST may be a new therapeutic target in patients with Ewing sarcoma. Cancer 2014;120:579–588. © 2014 American Cancer Society.
Origin of 5‐Hydroxymethylfurfural Stability in Water/Dimethyl Sulfoxide Mixtures
Authors: Tsilomelekis George , Josephson Tyler R. , Nikolakis Vladimiros , Caratzoulas Stavros
Published: January 2014

In the present work, we combined vibrational spectroscopy with electronic structure calculations to understand the solvation of HMF in DMSO, water, and DMSO/water mixtures and to provide insights into the observed hindrance of HMF rehydration and aldol condensation reactions if it is dissolved in DMSO/water mixtures. To achieve this goal, the attenuated total reflection FTIR spectra of a wide composition range of binary and ternary mixtures were measured, analyzed, and compared to the findings of ab initio DFT calculations. The effect of solvent on the HMF CO and OH vibrational modes reveals significant differences that are ascribed to different intermolecular interactions between HMF and DMSO or water. We also found that DMSO binds to HMF more strongly than water, and interactions with the HMF hydroxyl group are stronger than those with the HMF carbonyl group. We also showed the preferential solvation of HMF CO groups by DMSO if HMF is dissolved in DMSO/water mixed solvent. Frontier molecular orbital theory was used to examine the influence of the solvent on side reactions. The results show that HMF solvation by DMSO increases its LUMO energy, which reduces its susceptibility to nucleophilic attack and minimizes undesirable hydration and humin‐formation reactions. This result, together with the preferential solvation of HMF by DMSO, provide an explanation for the enhanced HMF stability in DMSO/water mixtures observed experimentally.
Performance of fiber delay‐line buffers in asynchronous packet‐based optical switching networks with wavelength conversion
Authors: Zhang Tao , Wang Jin
Published: January 2014

A major challenge in asynchronous packet‐based optical networks is packet contention, which occurs when two or more packets head to the same output at the same time. To resolve contention in the optical domain, two primary approaches are wavelength conversion and fiber delay line (FDL) buffering. In wavelength conversion, a contending packet can be converted from one wavelength to another in order to avoid conflict. In FDL buffering, contending packets can be delayed for a fixed amount of time. While the performance of wavelength conversion and FDL buffering has been evaluated extensively in synchronous networks with fixed‐sized packets, in this paper, we study the performance of FDL buffers in asynchronous packet‐based optical networks with wavelength conversion. An analytical model is proposed to evaluate the performance in terms of packet loss probability and average delay. Extensive simulation and analytical results show that, with appropriate settings, FDL buffers can perform much better in switches with wavelength conversion than in switches with no conversion. Copyright © 2014 John Wiley & Sons, Ltd.
Electronic and Steric Effects of the Peripheral Substitution in Deca‐ and Undecaaryl Metallocorroles
Authors: Gao Di , Canard Gabriel , Giorgi Michel , Vanloot Pierre , Balaban Teodor Silviu
Published: January 2014

Invited for the cover of this issue are chemists from the University of Aix Marseille, France. The cover image shows the saddling of the aromatic corrole macrocycle that occurs when the cavity of the corrole is metallated with a copper ion. This saddling is reinforced by bulky peripheral aryl groups, which modulate the electrochemical properties of deca‐ and undecaaryl copper corroles. The background is a view of the autonomous port of Marseille.
Human mitochondrial leucyl tRNA synthetase can suppress non cognate pathogenic mt‐tRNA mutations
Authors: Hornig‐Do Hue Tran , Montanari Arianna , Rozanska Agata , Tuppen Helen A , Almalki Abdulraheem A , Abg‐Kamaludin Dyg P , Frontali Laura , Francisci Silvia , Lightowlers Robert N , Chrzanowska‐Lightowlers Zofia M
Published: January 2014

Disorders of the mitochondrial genome cause a wide spectrum of disease, these present mainly as neurological and/or muscle related pathologies. Due to the intractability of the human mitochondrial genome there are currently no effective treatments for these disorders. The majority of the pathogenic mutations lie in the genes encoding mitochondrial tRNAs. Consequently, the biochemical deficiency is due to mitochondrial protein synthesis defects, which manifest as aberrant cellular respiration and ATP synthesis. It has previously been reported that overexpression of mitochondrial aminoacyl tRNA synthetases has been effective, in cell lines, at partially suppressing the defects resulting from mutations in their cognate mt‐tRNAs. We now show that leucyl tRNA synthetase is able to partially rescue defects caused by mutations in non‐cognate mt‐tRNAs. Further, a C terminal peptide alone can enter mitochondria and interact with the same spectrum of mt‐tRNAs as the entire synthetase, in intact cells. These data support the possibility that a small peptide could correct at least the biochemical defect associated with many mt‐tRNA mutations, inferring a novel therapy for these disorders.
The use of a Corophium volutator chronic sediment study to support the risk assessment of medetomidine for marine environments
Authors: Fox Michelle , Ohlauson Cecilia , Sharpe Alan D. , Brown Rebecca J.
Published: January 2014

Chronic sediment studies were conducted using the marine amphipod Corophium volutator as part of an environmental risk assessment of the novel antifouling compound medetomidine. Two studies were performed, starting with neonates of less than 7 d old. A 28-d study considered endpoints of survival and growth (length and wet wt) and a 76-d study looked at survival, growth (length and wet wt), and reproduction (number of gravid females and neonates). Medetomidine was dosed via the sediment at nominal test concentrations of 1.0 µg/kg, 3.2 µg/kg, 10 µg/kg, 32 µg/kg, and 100 µg/kg (dry wt). In the 28-d growth study, a significant increase in mortality was observed at 32 µg/kg and 100 µg/kg. In the 76-d reproduction study, there were significant adverse effects on survival (32 µg/kg and 100 µg/kg), growth (100 µg/kg), and reproduction (100 µg/kg). The overall lowest-observed-effect concentration was 32 µg/kg medetomidine. For this test substance the increased study duration did not increase the overall sensitivity of the test. The present study suggests that the predicted sediment environmental concentration (PECsediment) of 0.003 µg/kg for medetomidine would not be expected to cause adverse effects on the life history of C. volutator. Environ Toxicol Chem 2014;33:937–942. © 2014 SETAC
Effects of 17β-estradiol pollution on water microbial methane oxidation activity
Authors: Ruan Aidong , Zong Fengjiao , Zhao Ying , Liu Chenxiao , Chen Jing
Published: January 2014

17β-estradiol (17β-E2), a widespread and natural estrogen in the environment, has imposed a serious threat to the safety and function of aquatic ecosystems because of worsening pollution and high potential toxicity. In the present study, the authors focus on the impact of 17β-E2 pollution on water microbial methane oxidation function. The authors investigated the mechanism of its influence on water microbial activity and discuss the growth rate of methane-oxidizing bacteria. The results showed that 17β-E2 could significantly inhibit the function of water microbial methane oxidation. When 17β-E2 concentration was ≥5 ng L−1, the methane oxidation rate increased with increasing 17β-E2 and finally settled to a constant value. Furthermore, the authors found no significant linear correlation between 17β-E2 concentrations and its methane oxidation rate. However, increasing 17β-E2 dramatically improved water microbial community activity, because a significant or highly significant promotion in the generation rate of CO2 was measured. Moreover, within a certain period of time and at certain concentrations, positive linear correlation existed between water CO2 generation rate and 17β-E2 concentrations. In addition, the growth rate of culturable methane-oxidizing bacteria was promoted when 17β-E2 pollution concentration from 2 ng L−1 to 20 ng L−1. Therefore, 17β-E2 pollution can inhibit microbial methane oxidation function in water, which indirectly promotes the release of water methane and directly contributes to the rate of water-generated and released CO2. Specifically, 17β-E2 pollution can promote water emissions of greenhouse gases. Environ Toxicol Chem 2014;33:768–775. © 2014 SETAC
Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage
Authors: Seo Yeon Seok , Park Soo Young , Kim Moon Young , Kim Ju Hyun , Park Jun Yong , Yim Hyung Joon , Jang Byoung Kuk , Kim Hong Soo , Hahn Taeho , Kim Byung Ik , Heo Jeong , An Hyonggin , Tak Won Young , Baik Soon Koo , Han Kwang Hyub , Hwang Jae Seok , Park Sang Hoon , Cho Mong , Um Soon Ho
Published: January 2014

Vasoactive drugs are recommended to be started as soon as possible in suspected variceal bleeding, even before diagnostic endoscopy. However, it is still unclear whether the therapeutic efficacies of the various vasoactive drugs used are comparable. The aim of this prospective, multicenter, randomized, noninferiority trial was to characterize the effects of terlipressin, somatostatin, and octreotide when they are initiated before endoscopic treatment in patients with acute variceal bleeding. Patients with liver cirrhosis and significant upper gastrointestinal bleeding were randomly assigned to receive early administration of terlipressin, somatostatin, or octreotide, followed by endoscopic treatment. Patients with nonvariceal bleeding were excluded after endoscopy. The primary endpoint was 5-day treatment success, defined as control of bleeding without rescue treatment, rebleeding, or mortality, with a noninferiority margin of 0.1. In total, 780 patients with variceal bleeding were enrolled: 261 in the terlipressin group; 259 in the somatostatin group; and 260 in the octreotide group. At the time of initial endoscopy, active bleeding was noted in 43.7%, 44.4%, and 43.5% of these patients, respectively (P = 0.748), and treatment success was achieved by day 5 in 86.2%, 83.4%, and 83.8% (P = 0.636), with similar rates of control of bleeding without rescue treatment (89.7%, 87.6%, and 88.1%; P = 0.752), rebleeding (3.4%, 4.8%, and 4.4%; P = 0.739), or mortality (8.0%, 8.9%, and 8.8%; P = 0.929). The absolute values of the lower bound of confidence intervals for terlipressin versus somatostatin, terlilpressin versus octreotide, and octreotide versus somatostatin were 0.095, 0.090, and 0.065, respectively. Conclusion: Hemostatic effects and safety did not differ significantly between terlipressin, somatostatin, and octreotide as adjuvants to endoscopic treatment in patients with acute gastroesophageal variceal bleeding. (Hepatology 2014;60:954–963)
Tanshinone II A Inhibits Tat‐Induced HIV‐1 Transactivation Through Redox‐Regulated AMPK/Nampt Pathway
Authors: Zhang Hong‐Sheng , Chen Xin‐Yu , Wu Tong‐Chao , Zhang Feng‐Juan
Published: January 2014

Tat transactivating activity regulated by NAD+‐dependent histone deacetylase sirtuin1 (SIRT1) connects HIV transcription with the metabolic state of the cell. Nicotinamide phosphoribosyltransferase (Nampt) is a rate‐limiting enzyme in the mammalian NAD+ biosynthesis. Nampt, SIRT1, and AMPK were involved in inhibiting HIV‐1 transactivation through redox‐regulated pathway. Tanshinone II A is a main lipid‐soluble monomer derivative from the root of Salvia miltiorrhiza (Danshen) and tanshinone II A possess a variety of biological activities through redox signaling pathway. Here we investigated the effect of tanshinone II A on Tat‐induced HIV‐1 transactivation and the redox signaling pathway involved in it. As the results were shown, tanshinone II A reversed Tat‐induced reactive oxygen species (ROS) production and down‐regulation of glutathione (GSH) levels in TZM‐bl cells through up‐regulation of Nrf2 expression. Tanshinone II A reversed Tat‐induced inhibition of SIRT1 activity but not SIRT1 protein expression. Tanshinone II A reversed Tat‐induced inhibition of Nampt protein expression and depletion of NAD+ levels in TZM‐bl cells in a dose‐dependent manner. Tanshinone II A‐evoked Nampt expression was mediated by AMPK signaling pathway. Tanshinone II A inhibited Tat‐induced HIV‐1 LTR transactivation dependent on AMPK‐Nampt pathway. Collectively, our data provide new insights into understanding of the molecular mechanisms of tanshinone II A inhibited Tat‐regulated transcription, suggesting that targeting AMPK/Nampt/SIRT1 pathway could serve as new anti‐HIV‐1 agents. J. Cell. Physiol. 229: 1193–1201, 2014. © 2014 Wiley Periodicals, Inc.
Interleukin‐28b CC genotype predicts early treatment response and CT/TT genotypes predicts non‐response in patients infected with HCV genotype 3
Authors: Gupta Abhishak Chander , Trehanpati Nirupma , Sukriti Sukriti , Hissar Syed , Midha Vandana , Sood Ajit , Sarin Shiv K.
Published: January 2014

Response to antiviral therapy for hepatitis C virus (HCV) depends upon the genotype and host immune response. IL28b gene mutations have been shown to modulate host antiviral immune response against genotype 1. However, the predictive value of IL28b polymorphism in genotype 3 HCV patients is largely unknown. The association of IL28b polymorphism with virological response was studied in 356 patients with genotype 3 chronic HCV undergoing treatment with peg‐interferon and ribavirin and was compared with matched controls. IL28b genotyping followed by DNA sequencing was performed to identify the CC, CT, or TT genotypes. Two log reduction of HCV RNA at Day 7 (Quick Viral Response, QVR) and HCV RNA negativity at Day 28 (Rapid Viral Response, RVR) were analyzed with CC and non‐CC genotypes in addition to other predictors of response. The associations of alleles with the response patterns were predicted. Sustained viral response was seen in 250 (70.2%) patients and the IL28b genotype CC/CT/TT distribution was 61.1%; 30.5%; and 8.4%, respectively. The non‐CC genotypes were significantly higher in non‐responders when compared to responders (67.6% vs. 38.9%, P < 0.001). Interestingly, the rapid viral response in responders was observed in 72.7% with the CC genotype and in 27.2% with the non‐CC genotype (P < 0.001). Multivariate analysis showed CC genotype as an independent factor predicting the sustained viral response in patients infected with HCV genotype 3. In conclusion, the IL28b CT/TT genotype strongly correlates with treatment non‐response in patients infected with HCV genotype 3 and CC genotype of IL28b is associated with higher quick viral response. J. Med. Virol. 86:707–712, 2014. © 2014 Wiley Periodicals, Inc.