bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventing and Diagnosing Colorectal Cancer with a Limited Colonoscopy Resource
Authors: Güneş Evrim Didem , Örmeci Egemen Lerzan , Kunduzcu Derya
Published: February 2014

This paper explores how the capacity of colonoscopy services should be allocated for screening and diagnosis of colorectal cancer to improve health outcomes. Both of these services are important since screening prevents cancer by removing polyps, while diagnosis is required to start treatment for cancer. This paper first presents a basic compartmental model to illustrate the trade‐off between these two analytically. Further, a more realistic population dynamics model with resource constraints is introduced for colorectal cancer screening and analyzed numerically. The best resource allocation decisions are investigated with the objectives of minimizing mortality or incidence rates. We provide a sensitivity analysis with respect to policy and disease‐related parameters. We conclude that to minimize mortality, the capacity should be rationed to ensure that the wait for diagnosis is at reasonable levels. When the relevant performance measure is the incidence rate, screening is allocated more capacity compared to the case with mortality rate measure. We also show that benefits from increasing compliance to screening programs can only be realized if there is sufficient service capacity.
A Newsvendor Who Chooses Informational Effort
Authors: Marschak Thomas , George Shanthikumar J. , Zhou Junjie
Published: February 2014

We study a newsvendor who can acquire the services of a forecaster, or, more generally, an information gatherer (IG) to improve his information about demand. When the IG's effort increases, does the average ex ante order quantity rise or fall? Do average ex post sales rise or fall? Improvements in information technology and in the services offered by forecasters provide motivation for the study of these questions. Much depends on our model of the IG and his efforts. We study an IG who sends a signal to a classic single‐period newsvendor. The signal defines the newsvendor's posterior probability distribution on the possible demands and the newsvendor uses that posterior to calculate the optimal order. Each of the possible posteriors is a scale/location transform of the same base distribution. When the IG works harder, the average scale parameter drops. Higher IG effort is always useful to the newsvendor. We show that there is a critical value of order cost. For costs on one side of this value more IG effort leads to a higher average ex ante order and for costs on the other side to a lower average order. But for all costs, more IG effort leads to higher average ex post sales. We obtain analogous results for a “regret‐averse” newsvendor who suffers a penalty that is a nonlinear function of the discrepancy between quantity ordered and true demand.
Supplier Encroachment as an Enhancement or a Hindrance to Nonlinear Pricing
Authors: Li Zhuoxin , Gilbert Stephen M. , Lai Guoming
Published: February 2014

The objective of this study was to extend existing understanding of supplier encroachment to contexts in which there is information asymmetry and the supplier can use nonlinear pricing. Prior research has shown that supplier encroachment can mitigate double marginalization and thus benefit both the supplier and the reseller. However, under symmetric information, this benefit disappears if the supplier can use nonlinear pricing. In our model, the reseller observes the true market size while the supplier knows only the prior distribution, that is, a seemingly ideal setting for implementing mechanism design through nonlinear pricing. We first show that, because encroachment capability enables the supplier to make an ex post output decision, it fundamentally alters the structure of the optimal nonlinear pricing policy. In addition to the usual downward distortion effect, where the reseller may purchase less than the efficient quantity, we also have the possibility for upward distortion. Thus, under asymmetric information and nonlinear pricing, supplier encroachment has two opposing effects. On one hand, the ability to shift sales to the direct channel allows the supplier to reduce information rents with less sacrifice of efficiency; but on the other hand, by introducing the possibility of her own opportunistic behavior, it can result in upward distortion of the quantities sold through the reselling channel, which is a new source of inefficiency. Depending upon the relative efficiency of the reselling channel and the demand distribution, either of these two effects may dominate and the supplier's ability to encroach may either benefit or hurt both the supplier and the reseller.
The Effect of Language Differences and National Culture on Operational Process Compliance
Authors: Gray John V. , Massimino Brett
Published: February 2014

With increasing frequency, firms are locating their operations in disparate countries with distinct national cultures and languages. This study develops and empirically tests hypotheses relating an operation's process compliance performance to (1) the presence of a language difference between the location of the operation and that of headquarters and (2) the national culture of the location of the operation and that of headquarters. Employing an international sample of pharmaceutical manufacturing plants located primarily in Western nations, the analysis reveals that a language difference between the location of a plant and the firm's headquarters is consistently related to decreased process compliance at the plant level. Regarding national culture, only limited evidence of a direct relationship between national cultural dimensions (at either the plant or headquarters location) and process compliance exists. However, the analysis does suggest that cultural congruence between the location of the plant and that of headquarters can relate to improved compliance performance. Such a relationship depends on the specific national cultural dimension studied. While these results are obtained in a specific manufacturing setting, they potentially have implications for process compliance in any global operation.
An Analysis of Scoring and Buyer‐Determined Procurement Auctions
Authors: Santamaría Natalia
Published: February 2014

In procurement auctions, the object for sale is a contract, bidders are suppliers, and the bid taker is a buyer. The suppliers bidding for the contract are usually the current supplier (the incumbent) and a group of potential new suppliers (the entrants). As the buyer has an ongoing relationship with the incumbent, he needs to adjust the bids of the entrants to include non‐price attributes, such as the switching costs. The buyer can run a scoring auction, in which suppliers compete on the adjusted bids or scores, or, he can run a buyer‐determined auction, in which suppliers compete on the price, and the buyer adjusts a certain number of the bids with the non‐price attributes after the auction to determine the winner. Unless the incumbent has a significant cost advantage over the entrants, I find that the scoring auction yields a lower average cost for the buyer, if the non‐price attributes are available. If the non‐price attributes are difficult or expensive to obtain, the buyer could run a buyer‐determined auction adjusting only the lowest price bid.
The Impact of Contracts and Competition on Upstream Innovation in a Supply Chain
Authors: Wang Jingqi , Shin Hyoduk
Published: February 2014

We consider a supply chain with an upstream supplier who invests in innovation and a downstream manufacturer who sells to consumers. We study the impact of supply chain contracts with endogenous upstream innovation, focusing on three different contract scenarios: (i) a wholesale price contract, (ii) a quality‐dependent wholesale price contract, and (iii) a revenue‐sharing contract. We confirm that the revenue‐sharing contract can coordinate supply chain decisions including the innovation investment, whereas the other two contracts may result in underinvestment in innovation. However, the downstream manufacturer does not always prefer the revenue‐sharing contract; the manufacturer's profit can be higher with a quality‐dependent wholesale price contract than with a revenue‐sharing contract, specifically when the upstream supplier's innovation cost is low. We then extend our model to incorporate upstream competition between suppliers. By inviting upstream competition, with the wholesale price contract, the manufacturer can increase his profit substantially. Furthermore, under upstream competition, the revenue‐sharing contract coordinates the supply chain, and results in an optimal contract form for the manufacturer when suppliers are symmetric. We also analyze the case of complementary components suppliers, and show that most of our results are robust.
Defining Problems Fast and Slow: The U‐shaped Effect of Problem Definition Time on Project Duration
Authors: Choo Adrian S.
Published: February 2014

This study examines how time spent in problem definition affects problem solving in projects such as Six Sigma projects. Our hypotheses are tested using data collected from 1558 Six Sigma projects in a company. The results show evidence of a U‐shaped relationship between the amount of time spent in the Define phase and project duration. This finding suggests that spending too little time on problem definition potentially causes poor problem formulation, which leads to deficient problem solving and lengthens overall project time. On the other hand, too much time spent on problem definition can lead to unneeded delays in project completion due to diminishing returns on problem definition efforts. Furthermore, the optimal balance between spending too little and too much time depends on prior project experience and project complexity. Prior project experience reduced project completion time and weakened the U‐shaped effect. Conversely, complex projects took longer and appeared to show some evidence of a stronger U‐shaped effect; this suggests balancing the time spent in the Define phase was more challenging for complex projects. Our study also underscores the importance of managing project duration, as projects that were completed faster tended to be associated with higher project savings.
Fairness in Selling to the Newsvendor
Authors: Wu Xiaole , Niederhoff Julie A.
Published: February 2014

This paper studies the impact of fairness concerns on supply chain performance (SCP) in the two‐party newsvendor setting. We extend prior fairness analysis to a wide range of demand distributions, and also allow the degree and definition of fairness to assume a broader range of preferences than those in prior literature. Contrary to prior literature, we find that if the retailer's ideal allocation to the supplier is not sufficiently large, regardless of demand variability, a fair‐minded retailer makes no difference to system efficiency when facing a traditional profit‐maximizing supplier. Only when the retailer's ideal allocation to the supplier is above a threshold can the retailer's fairness concern improve the system efficiency for sufficiently high demand uncertainty. In order for the retailer's fairness concern to improve expected profits of both parties compared to the traditional supply chain case (win–win), the demand uncertainty cannot be too low, the retailer is not very averse to disadvantageous inequity, and his ideal allocation to the supplier is within a specific range. If only the supplier is concerned for fairness, the results range from worsening to improving (but not coordinating) the system and a win–win situation is impossible. Finally, when both the supplier and retailer are fair‐minded, SCP is improved unless both parties prefer to allocate small portions of system profit to the other. Again, win–win will be achieved only when the demand uncertainty is sufficiently high, the retailer's ideal allocation is within a certain range, and he is not very averse to disadvantageous inequity.
Optimal Sourcing and Lead‐Time Reduction under Evolutionary Demand Risk
Authors: deTreville Suzanne , Schürhoff Norman , Trigeorgis Lenos , Avanzi Benjamin
Published: February 2014

We develop a real‐options model for optimizing production and sourcing choices under evolutionary supply‐chain risk. We model lead time as an endogenous decision and calculate the cost differential required to compensate for the risk exposure coming from lead time. The shape of the resulting cost‐differential frontier reveals the term structure of supply‐chain risk premiums and provides guidance as to the potential value of lead‐time reduction. Under constant demand volatility, the break‐even cost differential increases in volatility and lead time at a decreasing rate, making incremental lead‐time reduction less valuable than full lead‐time reduction. Stochastic demand volatility increases the relative value of incremental lead‐time reduction. When demand has a heavy right tail, the value of lead‐time reduction depends on how extreme values of demand are incorporated into the forecasting process. The cost‐differential frontier is invariant to discount rates, making the cost of capital irrelevant for choosing between lead times. We demonstrate the managerial implications of the model by applying it first to the classic Sport‐Obermeyer case and then to a supplier‐selection problem faced by a global manufacturer.
Comparative analysis of gene expression under cold acclimation, deacclimation and reacclimation in Arabidopsis
Authors: Byun Youn‐Jung , Koo Mi‐Young , Joo Hye‐Joon , Ha‐Lee Young‐Mie , Lee Dong‐Hee
Published: February 2014

Cold acclimated plants show an elevated tolerance against subsequent cold stress. Such adaptation requires alterations in gene expression as well as physiological changes. We were interested in gene expression changes at the transcriptional level during adaptation processes. The patterns of transcriptional changes associated with cold acclimation, deacclimation and reacclimation in Arabidopsis leaves were characterized using the Coldstresschip. Gene expression profiles were further analyzed by ‘coexpressed gene sets’ using gene set enrichment analysis (GSEA). Genes involved in signal transduction through calcium, and cascades of kinases and transcription factor genes, were distinctively induced in the early response of cold acclimation. On the other hand, genes involved in antioxidation, cell wall biogenesis and sterol synthesis were upregulated in the late response of cold acclimation. After the removal of cold, the expression patterns of most genes rapidly returned to the original states. However, photosynthetic light‐harvesting complex genes and lipid metabolism‐related genes stayed upregulated in cold deacclimated plants compared to non‐treated plants. It is also notable that many well‐known cold‐inducible genes are slightly induced in reacclimation and their expression remains at relatively low levels in cold reacclimation compared to the expression during the first cold acclimation. The results in this study show the dynamic nature of gene expression occurring during cold acclimation, deacclimation and reacclimation. Our results suggest that there is a memory of cold stress and that the ‘memory of cold stress’ is possibly due to elevated photosynthetic efficiency, modified lipid metabolism, increased calcium signaling, pre‐existing defense protein made during first cold acclimation and/or modified signal transduction from pre‐existing defense protein.
Dermal Versus Total Uptake of Benzene from Mineral Spirits Solvent During Parts Washing
Authors: Bogen Kenneth T. , Sheehan Patrick J.
Published: February 2014

Quantitative approaches to assessing exposure to, and associated risk from, benzene in mineral spirits solvent (MSS), used widely in parts washing and degreasing operations, have focused primarily on the respiratory pathway. The dermal contribution to total benzene uptake from such operations remains uncertain because measuring in vivo experimental dermal uptake of this volatile human carcinogen is difficult. Unprotected dermal uptake involves simultaneous sustained immersion events and transient splash/wipe events, each yielding residues subject to evaporation as well as dermal uptake. A two‐process dermal exposure framework to assess dermal uptake to normal and damaged skin was applied to estimate potential daily dermal benzene dose (Dskin) to workers who used historical or current formulations of recycled MSS in manual parts washers. Measures of evaporation and absorption of MSS dermally applied to human subjects were modeled to estimate in vivo dermal uptake of benzene in MSS. Uncertainty and interindividual variability in Dskin was characterized by Monte Carlo simulation, conditioned on uncertainty and/or variability estimated for each model input. Dermal exposures are estimated to average 33% of total (inhalation + dermal) benzene parts washing dose, with approximately equal predicted portions of dermal dose due to splash/wipe and to continuous contact with MSS. The estimated median (95th percentile) dermal and total daily benzene doses from parts washing are: 0.0069 (0.024) and 0.025 (0.18) mg/day using current, and 0.027 (0.085) and 0.098 (0.69) mg/day using historical, MSS solvents, respectively.
Inference for Stable Isotope Mixing Models: A Study of the Diet of Dunlin
Authors: Erhardt Erik Barry , Bedrick Edward J.
Published: February 2014

Stable isotope sourcing is used to estimate proportional contributions of sources to a mixture, such as in the analysis of animal diets and plant nutrient use. Statistical methods for inference on the diet proportions by using stable isotopes have focused on the linear mixing model. Existing frequentist methods assume that the diet proportion vector can be uniquely solved for in terms of one or two isotope ratios. We develop large sample methods that apply to an arbitrary number of isotope ratios, assuming that the linear mixing model has a unique solution or is overconstrained. We generalize these methods to allow temporal modelling of the population mean diet, assuming that isotope ratio response data are collected over time. The methodology is motivated by a study of the diet of dunlin, a small migratory seabird.
Cell‐Surface Bound Nonreceptors and Signaling Morphogen Gradients
Authors: Wan Frederic Y. M.
Published: February 2014

The patterning of many developing tissues is orchestrated by gradients of signaling morphogens. Included among the molecular events that drive the formation of morphogen gradients are a variety of elaborate regulatory interactions. Such interactions are thought to make gradients robust, i.e., insensitive to change in the face of genetic or environmental perturbations. However just how this is accomplished is a major unanswered question. Recently extensive numerical simulations suggest that robustness of signaling gradients can be achieved through morphogen degradation mediated by cell surface bound nonsignaling receptor molecules (or nonreceptors for short) such as heparan sulfate proteoglycans. The present paper provides a mathematical validation of the results from the aforementioned numerical experiments. Extension of a basic extracellular model to include reversible binding with nonreceptors synthesized at a prescribed rate and mediated morphogen degradation shows that the signaling gradient diminishes with increasing concentration of cell‐surface nonreceptors. Perturbation and asymptotic solutions obtained for (i) low (receptor and nonreceptor) occupancy, and (ii) high nonreceptor concentration permit more explicit delineation of the effects of nonreceptors on signaling gradients and facilitate the identification of scenarios in which the presence of nonreceptors may or may not be effective in promoting robustness.
The Relation of Cognitive Reappraisal and Expressive Suppression to Suicidal Ideation and Suicidal Desire
Authors: Forkmann Thomas , Scherer Anne , Böcker Maren , Pawelzik Markus , Gauggel Siegfried , Glaesmer Heide
Published: February 2014

The differential relations between the emotion regulation strategies “cognitive reappraisal” and “expressive suppression” and suicidality in a mixed inpatient sample (N = 232, 69.4% female) of a German psychotherapeutic hospital were examined. Patients filled in the Emotion Regulation Questionnaire and items on suicidal ideation and desire. A structural equation model fitted the data (RMSEA = .044; CFI = .96) and revealed that “expressive suppression” significantly predicted increased suicidal ideation. Moderation analysis showed that results were independent from a current depressive episode. Potential implications for psychotherapeutic treatment of suicidality are discussed.
Der schweizerische Bundesstaat von 1848 bis 1874: Mehrheits‐ oder Konsensusdemokratie?
Authors: Wirz Rolf
Published: February 2014

Abstract (deutsch)

Der vorliegende Beitrag geht der Frage nach, ob die schweizerische Demokratie bereits ab der Bundesstaatsgründung im Jahr 1848 eine ausgeprägte Konsensusdemokratie war. Zur Beantwortung dieser Fragestellung bedient sich die Studie des Konzepts von Arend Lijphart () mit der Unterscheidung von Mehrheits‐ und Konsensusdemokratie. Anhand von Literatur‐ und Dokumentenanalysen wurden Lijpharts Indikatoren für den schweizerischen Bundesstaat von 1848–1874 codiert. Die Ergebnisse zeigen, dass das politische System der neu gegründeten Schweiz auf Lijpharts Demokratiekarte insbesondere auf der horizontalen Machtteilungsdimension wie erwartet sehr nahe an der Position der USA zu liegen kommt.
Evaluating linkage to care for hypertension after community‐based screening in rural Uganda
Authors: Kotwani Prashant , Balzer Laura , Kwarisiima Dalsone , Clark Tamara D. , Kabami Jane , Byonanebye Dathan , Bainomujuni Bob , Black Douglas , Chamie Gabriel , Jain Vivek , Thirumurthy Harsha , Kamya Moses R. , Geng Elvin H. , Petersen Maya L. , Havlir Diane V. , Charlebois Edwin D.
Published: February 2014

Objectives

To determine the frequency and predictors of hypertension linkage to care after implementation of a linkage intervention in rural Uganda.

Methods

During a multidisease screening campaign for HIV, diabetes and hypertension in rural Uganda, hypertensive adults received education, appointment to a local health facility and travel voucher. We measured frequency and predictors of linkage to care, defined as visiting any health facility for hypertension management within 6 months. Predictors of linkage to care were calculated using collaborative‐targeted maximum likelihood estimation (C‐TMLE). Participants not linking were interviewed using a standardised instrument to determine barriers to care.

Results

Over 5 days, 2252 adults were screened for hypertension and 214 hypertensive adults received a linkage intervention for further management. Of these, 178 (83%) linked to care within 6 months (median = 22 days). Independent predictors of successful linkage included older age, female gender, higher education, manual employment, tobacco use, alcohol consumption, hypertension family history and referral to local vs. regional health centre. Barriers for patients who did not see care included expensive transport (59%) and feeling well (59%).

Conclusions

A community health campaign that offered hypertension screening, education, referral appointment and travel voucher achieved excellent linkage to care (83%). Young adults, men and persons with low levels of formal education were among those least likely to seek care.
Glutamate receptors in the nucleus tractus solitarius contribute to ventilatory acclimatization to hypoxia in rat
Authors: Pamenter Matthew E. , Carr J. Austin , Go Ariel , Fu Zhenxing , Reid Stephen G. , Powell Frank L.
Published: February 2014

Key points

Ventilation increases more with chronic than acute hypoxia and does not return to control levels when normoxia is restored, indicating plasticity in the reflexes that control breathing.

Glutamate is the primary excitatory neurotransmitter between arterial chemoreceptors that sense hypoxia and neural circuits that control breathing in the brainstem.

We microinjected specific glutamate receptor antagonists into the brainstem of awake unrestrained rats and found NMDA‐type glutamate receptors explain increased ventilatory sensitivity to hypoxia after chronic hypoxia. AMPA‐type glutamate receptors mediate increased ventilatory drive in normoxia after chronic hypoxia, as well as increased ventilation in acute hypoxia after chronic hypoxia and in control conditions.

Phosphorylation of AMPA and NMDA receptors is increased by chronic hypoxia.

The results indicate that plasticity in different glutamate receptors have unique effects on the reflexes that control breathing in chronic hypoxia and may share cellular mechanisms with other models of neural plasticity.

When exposed to a hypoxic environment the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time‐dependent increase in ventilation occurs, which increases the HVR. This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. Currently these mechanisms of HVR plasticity are unknown and we hypothesized that they involve glutamatergic synapses in the nucleus tractus solitarius (NTS), where afferent endings from arterial chemoreceptors terminate. To test this, we treated rats held in normoxia (CON) or 10% O2 (CSH) for 7 days and measured ventilation in conscious, unrestrained animals before and after microinjecting glutamate receptor agonists and antagonists into the NTS. In normoxia, AMPA increased ventilation 25% and 50% in CON and CSH, respectively, while NMDA doubled ventilation in both groups (P < 0.05). Specific AMPA and NMDA receptor antagonists (NBQX and MK801, respectively) abolished these effects. MK801 significantly decreased the HVR in CON rats, and completely blocked the acute HVR in CSH rats but had no effect on ventilation in normoxia. NBQX decreased ventilation whenever it was increased relative to normoxic controls; i.e. acute hypoxia in CON and CSH, and normoxia in CSH. These results support our hypothesis that glutamate receptors in the NTS contribute to plasticity in the HVR with CSH. The mechanism underlying this synaptic plasticity is probably glutamate receptor modification, as in CSH rats the expression of phosphorylated NR1 and GluR1 proteins in the NTS increased 35% and 70%, respectively, relative to that in CON rats.
Prediction of the NOx Emissions of a Swirl Burner in Partially and Fully Premixed Mode on the Basis of Water Channel Laser Induced Fluorescence and Particle Image Velocimetry Measurements
Authors: Sangl J. , Mayer C. , Sattelmayer T.
Published: February 2014

The paper describes the development and validation of an efficient and cost effective method for the prediction of the NOx emissions of turbulent gas turbine burners in the early burner design phases, which are usually focused on the optimization of the swirler aerodynamics and the fuel-air mixing. Since the method solely relies on nonreacting tests of burner models in the water channel, it can be applied before any test equipment for combustion experiments exists. In order to achieve optimum similarity of fuel-air mixing in the water channel tests with engine operation the model is operated at the engine momentum ratio. During the laser induced fluorescence (LIF) measurements the water flow representing the fuel is doped with fluorescent dye, a plane perpendicular to the length axis near the burner exit plane is illuminated with a 5W Ar-ion laser, and the fluorescence is recorded with a video camera from downstream. From the video sequence,s the local probability density functions (PDF) of the dye concentration fluctuations are calculated from the data. Furthermore, the time mean velocity fields are measured with particle image velocimetry (PIV). The PDFs of the local equivalence ratio are derived from the LIF data. Assuming flamelets, the NOx generation in the entire equivalence ratio range observed in the water channel tests is computed using the unstrained freely propagating one-dimensional flame model in Cantera and the GRI3.0 reaction scheme. Although neither flame stretch nor post flame NOx generation were considered, the computed NOx values were in excellent agreement with the experimental data from perfectly premixed combustion experiments. The local time averaged NOx mole fraction is obtained by integrating the flamelet NOx over the mixture PDF. Finally the global NOx emission of the burner at the considered operating point is obtained by spatial integration, considering the measured velocity field. The method was validated using a conical swirl burner with two fuel injection stages, allowing the degree of premixedness to be adjusted over a wide range, depending on the specific fuel injection scenario. For the case with fuel injection along the air inlet slots NOx values slightly above the minimum NOx limit for perfectly premixed combustion were computed. This is consistent with the emission measurements and indicates the finite mixing quality of this injection method. In the partially premixed regime the configurations with potential for low NOx emissions were reliably identified with the LIF and PIV based water channel method. The method also shows the steep increase of the NOx emissions with the decreasing degree of premixing observed in the experiments, however, quantitative predictions would have required a postprocessing of the data from the LIF mixing study with a higher spatial resolution than available.
Developing Movement Efficiency Between 7 and 9 Years of Age
Authors: Bosga-Stork Ida Maria , Bosga Jurjen , Meulenbroek Ruud G.J.
Published: February 2014

This longitudinal study examined the movement efficiency of typically developing children between 7 and 9 years of age by scrutinizing their movement amplitudes and frequencies as they settled into a loop-writing task in which both parameters were prescribed. It was hypothesized that during the first three grades at primary school children would show increasing efficiency in exploiting the inverse relationship between movement amplitude and frequency when adjusting their movement errors. Whereas a clear developmental trend showed increasing efficiency with respect to the way in which the primary school children met the amplitude constraints, a more variable pattern was found for the age-dependent adjustments to the frequency requirements. At the level of parameter-error corrections from one cycle to the next, a marginal developmental trend was observed. Results are discussed in terms of contrasting effects between educational targets and movement-efficiency principles.
Online Manual Movement Adjustments in Response to Target Position Changes and Apparent Target Motion
Authors: Wijdenes Leonie Oostwoud , Brenner Eli , Smeets Jeroen B.J.
Published: February 2014

This study set out to determine whether the fastest online hand movement corrections are only responses to changing judgments of the targets’ position or whether they are also influenced by the apparent target motion. Introducing a gap between when a target disappears and when it reappears at a new position in a double-step paradigm disrupts the apparent motion, so we examined the influence of such a gap on the intensity of the response. We found that responses to target perturbations with disrupted apparent motion were less vigorous. The response latency was 10 ms shorter when there was a gap, which might be related to the gap effect that has previously been described for initiating eye and hand movements.
Interconnected Network Motifs Control Podocyte Morphology and Kidney Function
Authors: Azeloglu Evren U. , Hardy Simon V. , Eungdamrong Narat John , Chen Yibang , Jayaraman Gomathi , Chuang Peter Y. , Fang Wei , Xiong Huabao , Neves Susana R. , Jain Mohit R. , Li Hong , Ma’ayan Avi , Gordon Ronald E. , He John Cijiang , Iyengar Ravi
Published: February 2014

Integrated network analysis and dynamical modeling predict intervention strategies to reverse kidney damage.
Coordinating the Clock
Authors: Ray L. Bryan
Published: February 2014

Flies use a mechanosensory organ to sense a low-frequency vibration and reset the brain’s biological clock.
Cyclin C Moves Out of the Nucleus
Authors: VanHook Annalisa M.
Published: February 2014

The transcriptional repressor cyclin C leaves the nucleus to promote mitochondrial fission.
Activating mTOR with Ral Instead of Rheb
Authors: Gough Nancy R.
Published: February 2014

Lack of a key regulatory complex in worms leads to the identification of a previously unknown regulatory mechanism for mTOR in mammalian cells.
In Vitro
Activities of Dermaseptins K
4
S
4
and K
4
K
20
S
4
against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa Planktonic Growth and Biofilm Formation
Authors: Zaïri Amira , Ferrières Lionel , Latour-Lambert Patricia , Beloin Christophe , Tangy Frédéric , Ghigo Jean-Marc , Hani Khaled
Published: February 2014

The rising number of infections caused by biofilm formation and the difficulties associated with their treatment by conventional antimicrobial therapies have led to an intensive search for novel antibiofilm agents. Dermaseptins are antimicrobial peptides with a number of attractive properties that might offer alternative therapies against resistant microorganisms. In this study, we synthesized a set of dermaseptin-derived peptides and evaluated their activities against Gram-positive and Gram-negative bacterial biofilm formation. All dermaseptin-derived peptides demonstrated concentration-dependent antibiofilm activities at microgram concentrations, and their activities were dependent on the nature of the peptides, with the highest levels of activity being exhibited by highly charged molecules. Fluorescent binding and confocal microscopy demonstrated that dermaseptin K
4
S
4
, a substituted derivative of the native molecule S
4
, significantly decreased the viability of planktonic and surface-attached bacteria and stopped biofilm formation under dynamic flow conditions. Cytotoxicity assays with HeLa cells showed that some of the tested peptides were less cytotoxic than current antibiotics. Overall, these findings indicate that dermaseptin derivatives might constitute new lead structures for the development of potent antibiofilm agents.
Factors That Cause Trimethoprim Resistance in Streptococcus pyogenes
Authors: Bergmann René , van der Linden Mark , Chhatwal Gursharan S. , Nitsche-Schmitz D. Patric
Published: February 2014

The use of trimethoprim in treatment of
Streptococcus pyogenes
infections has long been discouraged because it has been widely believed that this pathogen is resistant to this antibiotic. To gain more insight into the extent and molecular basis of trimethoprim resistance in
S. pyogenes
, we tested isolates from India and Germany and sought the factors that conferred the resistance. Resistant isolates were identified in tests for trimethoprim or trimethoprim-sulfamethoxazole (SXT) susceptibility. Resistant isolates were screened for the known horizontally transferable trimethoprim-insensitive dihydrofolate reductase (
dfr
) genes
dfrG
,
dfrF
,
dfrA
,
dfrD
, and
dfrK
. The nucleotide sequence of the intrinsic
dfr
gene was determined for resistant isolates lacking the horizontally transferable genes. Based on tentative criteria, 69 out of 268 isolates (25.7%) from India were resistant to trimethoprim. Occurring in 42 of the 69 resistant isolates (60.9%),
dfrF
appeared more frequently than
dfrG
(23 isolates; 33.3%) in India. The
dfrF
gene was also present in a collection of SXT-resistant isolates from Germany, in which it was the only detected trimethoprim resistance factor. The
dfrF
gene caused resistance in 4 out of 5 trimethoprim-resistant isolates from the German collection. An amino acid substitution in the intrinsic dihydrofolate reductase known from trimethoprim-resistant
Streptococcus pneumoniae
conferred resistance to
S. pyogenes
isolates of
emm
type 102.2, which lacked other aforementioned
dfr
genes. Trimethoprim may be more useful in treatment of
S. pyogenes
infections than previously thought. However, the factors described herein may lead to the rapid development and spread of resistance of
S. pyogenes
to this antibiotic agent.
Phenethyl Isothiocyanate Inhibits Shiga Toxin Production in Enterohemorrhagic Escherichia coli by Stringent Response Induction
Authors: Nowicki Dariusz , Maciąg-Dorszyńska Monika , Kobiela Wioletta , Herman-Antosiewicz Anna , Węgrzyn Alicja , Szalewska-Pałasz Agnieszka , Węgrzyn Grzegorz
Published: February 2014

The pathogenicity of enterohemorrhagic
Escherichia coli
(EHEC) depends on production of Shiga toxins, which are encoded by
stx
genes located in the genomes of lambdoid prophages. Efficient expression of these genes requires prophage induction and lytic development of phages. Treatment of EHEC infections is problematic due to not only the resistance of various strains to antibiotics but also the fact that many antibiotics cause prophage induction, thus resulting in high-level expression of
stx
genes. Here we report that
E. coli
growth, Shiga toxin-converting phage development, and production of the toxin by EHEC are strongly inhibited by phenethyl isothiocyanate (PEITC). We demonstrate that PEITC induces the stringent response in
E. coli
that is mediated by massive production of a global regulator, guanosine tetraphosphate (ppGpp). The stringent response induction arises most probably from interactions of PEITC with amino acids and from amino acid deprivation-mediated activation of ppGpp synthesis. In mutants unable to synthesize ppGpp, development of Shiga toxin-converting phages and production of Shiga toxin are significantly enhanced. Therefore, ppGpp, which appears at high levels in bacterial cells after stimulation of its production by PEITC, is a negative regulator of EHEC virulence and at the same time efficiently inhibits bacterial growth. This is in contrast to stimulation of virulence of different bacteria by this nucleotide reported previously by others.
Sustained Delivery of Commensal Bacteria from Pod-Intravaginal Rings
Authors: Gunawardana Manjula , Mullen Madeline , Yoo Jennifer , Webster Paul , Moss John A. , Baum Marc M.
Published: February 2014

Topical administration of live commensal bacteria to the vaginal tract holds significant potential as a cost-effective strategy for the treatment of sexually transmitted infections and the delivery of mucosal vaccines. Probiotic-releasing intravaginal rings (IVRs) embody significant theoretical advantages over traditional daily-dosage forms, such as sustained and controlled delivery leading to improved adherence to therapy compared to that of frequent dosing. The conventional IVR designs, however, are not amenable to the delivery of live bacteria. We have developed a novel pod-IVR technology where polymer-coated tablets (“pods”) of
Lactobacillus gasseri
strain ATCC 33323, a commensal microorganism of human origin, are embedded in silicone IVRs. The release rate of bacterial cells is controlled by the diameter of a delivery channel that exposes a portion of the pod to external fluids.
In vitro
studies demonstrated that the prototype devices released between 1.1 × 10
7
and 14 × 10
7
cells per day for up to 21 days in a controlled sustained fashion with stable burst-free release kinetics. The daily release rates were correlated with the cross-sectional area of the delivery channel. Bacteria in the IVR pods remained viable throughout the
in vitro
studies and formed biofilms on the surfaces of the devices. This proof-of-principle study represents the first demonstration of a prolonged, sustained release of bacteria from an intravaginal device and warrants further investigation of this device as a nonchemotherapeutic agent for the restoration and maintenance of normal urogenital flora.
Mutations within the
rplD
Gene of Linezolid-Nonsusceptible Streptococcus pneumoniae Strains Isolated in the United States
Authors: Dong W. , Chochua S. , McGee L. , Jackson D. , Klugman K. P. , Vidal J. E.
Published: February 2014

Three invasive
Streptococcus pneumoniae
strains nonsusceptible to linezolid were isolated in the United States between 2001 and 2012 from the CDC's Active Bacterial Core surveillance. Linezolid binds ribosomal proteins where structural changes within its target site may confer resistance. Our study identified mutations and deletions near the linezolid binding pocket of two of these strains within the
rplD
gene, which encodes ribosomal protein L4. Mutations in the 23S rRNA alleles or the
rplV
gene were not detected.
Bactericidal Activity of
N
-Chlorotaurine against Biofilm-Forming Bacteria Grown on Metal Disks
Authors: Coraça-Huber Débora C. , Ammann Christoph G. , Fille Manfred , Hausdorfer Johann , Nogler Michael , Nagl Markus
Published: February 2014

Many orthopedic surgeons consider surgical irrigation and debridement with prosthesis retention as a treatment option for postoperative infections. Usually, saline solution with no added antimicrobial agent is used for irrigation. We investigated the activity of
N
-chlorotaurine (NCT) against various biofilm-forming bacteria
in vitro
and thereby gained significant information on its usability as a soluble and well-tolerated active chlorine compound in orthopedic surgery. Biofilms of
Staphylococcus aureus
were grown on metal alloy disks and in polystyrene dishes for 48 h. Subsequently, they were incubated for 15 min to 7 h in buffered solutions containing therapeutically applicable concentrations of NCT (1%, 0.5%, and 0.1%; 5.5 to 55 mM) at 37°C. NCT inactivated the biofilm in a time- and dose-dependent manner. Scanning electron microscopy revealed disturbance of the biofilm architecture by rupture of the extracellular matrix. Assays with reduction of carboxanilide (XTT) showed inhibition of the metabolism of the bacteria in biofilms. Quantitative cultures confirmed killing of
S. aureus
,
Staphylococcus epidermidis
, and
Pseudomonas aeruginosa
biofilms on metal alloy disks by NCT. Clinical isolates were slightly more resistant than ATCC type strains, but counts of CFU were reduced at least 10-fold by 1% NCT within 15 min in all cases. NCT showed microbicidal activity against various bacterial strains in biofilms. Whether this can be transferred to the clinical situation should be the aim of future studies.
PrtR Homeostasis Contributes to Pseudomonas aeruginosa Pathogenesis and Resistance against Ciprofloxacin
Authors: Sun Ziyu , Shi Jing , Liu Chang , Jin Yongxin , Li Kewei , Chen Ronghao , Jin Shouguang , Wu Weihui
Published: February 2014

Pseudomonas aeruginosa
is an opportunistic pathogen that causes acute and chronic infections in humans. Pyocins are bacteriocins produced by
P. aeruginosa
that are usually released through lysis of the producer strains. Expression of pyocin genes is negatively regulated by PrtR, which gets cleaved under SOS response, leading to upregulation of pyocin synthetic genes. Previously, we demonstrated that PrtR is required for the expression of type III secretion system (T3SS), which is an important virulence component of
P. aeruginosa
. In this study, we demonstrate that mutation in
prtR
results in reduced bacterial colonization in a mouse acute pneumonia model. Examination of bacterial and host cells in the bronchoalveolar lavage fluids from infected mice revealed that expression of PrtR is induced by reactive oxygen species (ROS) released by neutrophils. We further demonstrate that treatment with hydrogen peroxide or ciprofloxacin, known to induce the SOS response and pyocin production, resulted in an elevated PrtR mRNA level. Overexpression of PrtR by a
tac
promoter repressed the endogenous
prtR
promoter activity, and electrophoretic mobility shift assay revealed that PrtR binds to its own promoter, suggesting an autorepressive mechanism of regulation. A high level of PrtR expressed from a plasmid resulted in increased T3SS gene expression during infection and higher resistance against ciprofloxacin. Overall, our results suggest that the autorepression of PrtR contributes to the maintenance of a relatively stable level of PrtR, which is permissive to T3SS gene expression in the presence of ROS while increasing bacterial tolerance to stresses, such as ciprofloxacin, by limiting pyocin production.
Type I Interferons Promote Severe Disease in a Mouse Model of Lethal Ehrlichiosis
Authors: Zhang Yubin , Thai Vinh , McCabe Amanda , Jones Maura , MacNamara Katherine C.
Published: February 2014

Human monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the order
Rickettsiales
. HME disease can range from mild to a fatal, toxic shock-like syndrome, yet the mechanisms regulating pathogenesis are not well understood. We define a central role for type I interferons (alpha interferon [IFN-α] and IFN-β) in severe disease in a mouse model of fatal ehrlichiosis caused by
Ixodes ovatus
Ehrlichia
(IOE). IFN-α and IFN-β were induced by IOE infection but not in response to a less virulent strain,
Ehrlichia muris
. The major sources of type I IFNs during IOE infection were plasmacytoid dendritic cells and monocytes. Mice lacking the receptor for type I IFNs (
Ifnar
deficient) or neutralization of IFN-α and IFN-β resulted in a reduced bacterial burden.
Ifnar
-deficient mice exhibited significantly increased survival after IOE infection, relative to that of wild-type (WT) mice, that correlated with increased type II IFN (IFN-γ) production. Pathogen-specific antibody responses were also elevated in
Ifnar
-deficient mice, and this required IFN-γ. Remarkably, increased IFN-γ and IgM were not essential for protection in the absence of type I IFN signaling. The direct effect of type I IFNs on hematopoietic and nonhematopoietic cells was evaluated in bone marrow chimeric mice. We observed that chimeric mice containing
Ifnar
-deficient hematopoietic cells succumbed to infection early, whereas
Ifnar
-deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-α receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infection
in vivo
and promote severe disease.
Intradural extramedullary and intracranial tuberculomas with concurrent communicating syringomyelia
Authors: Sharma Bhawna , Nagpal Kadam , Handa Rahul , Gupta Pankaj
Published: February 2014

Tuberculosis is the most common chronic central nervous system infection in developing countries like India. Non-osseous spinal cord involvement is a rare manifestation of tuberculosis. The use of MRI, as an imaging modality of choice, has revolutionised the imaging of tuberculomas with reasonable certainty and thereby avoiding unnecessary surgical intervention. We report an unusual presentation of intradural extramedullary and intracranial tuberculomas with communicating syringomyelia complicated with tubercular meningitis.
Weismann-Netter-Stuhl syndrome: report of two cases and treatment
Authors: Gupta Pratyush , Mittal Ravi , Mittal Samarth , Shankar Vivek
Published: February 2014

Weismann-Netter-Stuhl syndrome is a rarely reported cause of bowed legs; hence a thorough clinical and radiological examination is needed for its diagnosis. In view of the paucity of reports guiding the treatment of the deformity, we propose a one-level/two-level osteotomy with intramedullary nail fixation as a treatment modality for the tibial bowing.
Early vein graft failure leading to acute myocardial infarction, dehiscence and haemopericardium treated by percutaneous coil embolisation and balloon tamponade
Authors: Kanakadandi Uday , Huang Juxiang , Lee Kwan
Published: February 2014

Early vein graft failure is a well-described early complication of coronary artery bypass grafting. Revascularisation with emergency percutaneous coronary intervention (PCI) may limit the extent of myocardial damage and is associated with lower procedural complications compared than with emergency redo bypass surgery. We describe a case of an early saphenous vein graft (SVG) thrombosis presenting as an inferior ST-elevation to our non-surgical PCI site, complicated by SVG graft dehiscence leading to cardiac tamponade, which we treated with coil embolisation and balloon tamponade during the patient's transfer to a surgical facility for emergent haemopericardium evacuation.