bluuebunny/crossref_metadata_2025 huggingface dataset:
The transcription factor PPARα is overexpressed and is associated with a favourable prognosis in IDH‐wildtype primary glioblastoma
Authors: Haynes Harry R , White Paul , Hares Kelly M , Redondo Juliana , Kemp Kevin C , Singleton William G B , Killick‐Cole Clare L , Stevens Jonathan R , Garadi Krishnakumar , Guglani Sam , Wilkins Alastair , Kurian Kathreena M
Published: December 2016

Aims

PPARα agonists are in current clinical use as hypolipidaemic agents and show significant antineoplastic effects in human glioblastoma models. To date however, the expression of PPARα in large‐scale glioblastoma datasets has not been examined. We aimed to investigate the expression of the transcription factor PPARα in primary glioblastoma, the relationship between PPARα expression and patients’ clinicopathological features and other molecular markers associated with gliomagenesis.

Methods and results

With protein immunoblotting techniques and reverse transcription quantitative real‐time PCR, PPARα was found to be significantly overexpressed in glioblastoma compared with control brain tissue (P = 0.032 and P = 0.005). PPARA gene expression was found to be enriched in the classical glioblastoma subtype within The Cancer Genome Atlas (TCGA) dataset. Although not associated with overall survival when assessed by immunohistochemistry, cross‐validation with the TCGA dataset and multivariate analyses identified PPARA gene expression as an independent prognostic marker for overall survival (P = 0.042). Finally, hierarchical clustering revealed novel, significant associations between high PPARA expression and a putative set of glioblastoma molecular mediators including EMX2, AQP4, and NTRK2.

Conclusions

PPARα is overexpressed in primary glioblastoma and high PPARA expression functions as an independent prognostic marker in the glioblastoma TCGA dataset. Further studies are required to explore genetic associations with high PPARA expression and to analyse the predictive role of PPARα expression in glioblastoma models in response to PPARα agonists.
Two‐node‐connected star problem
Authors: Recoba Rodrigo , Robledo Franco , Romero Pablo , Viera Omar
Published: December 2016

In this study, a two‐node‐connected star problem (2NCSP) is introduced. We are given a simple graph and internal and external costs for each link of the graph. The goal is to find the minimum‐cost spanning subgraph, where the core is two‐node‐connected and the remaining external nodes are connected to the core. First, we show that the 2NCSP belongs to the class of NP‐hard computational problems. Therefore, a greedy randomized adaptive search procedure (GRASP) heuristic is developed, enriched with a variable neighborhood descent (VND). The neighborhood structures include exact integer linear programming models to find the best paths and two‐node‐connected replacements, as well as a shaking operation in order to prevent being trapped in a local minima. The ring star problem (RSP) represents a relevant model in network optimization, where the core is a ring instead of an arbitrary two‐node‐connected graph. We contrast our GRASP/VND methodology with a previous reference work on the RSP in order to highlight the effectiveness of our heuristic. The heuristic is competitive, and the best results produced for several instances so far are under study. In this study, a discussion of the results and trends for future work are provided.
Fragmented QRS Is a Novel Risk Factor for Ventricular Arrhythmic Events After Receiving Cardiac Resynchronization Therapy in Nonischemic Cardiomyopathy
Authors: IGARASHI MIYAKO , TADA HIROSHI , YAMASAKI HIRO , KUROKI KENJI , ISHIZU TOMOKO , SEO YOSHIHIRO , MACHINO TAKESHI , MURAKOSHI NOBUYUKI , SEKIGUCHI YUKIO , NOGUCHI YUICHI , NOGAMI AKIHIKO , AONUMA KAZUTAKA
Published: December 2016

Fragmented QRS and Ventricular Arrhythmias After CRT

Introduction

A fragmented QRS (fQRS) is reported to be associated with a poor prognosis or sudden cardiac death (SCD) in patients with Brugada syndrome or ischemic heart disease. However, no studies have clarified the impact of the presence of an fQRS on SCD or ventricular arrhythmic events in patients receiving cardiac resynchronization therapy (CRT). This study aimed to clarify this point in patients with nonischemic cardiomyopathy.

Methods and Results

This study included 137 heart failure patients with nonischemic cardiomyopathy who received CRT (NYHA functional class: II/III/IV = 25/84/28). The 12‐lead ECGs before and after CRT were analyzed. The presence of an fQRS was decided in accordance with the definition in previous papers. Before the CRT, an fQRS was observed in 67 patients (fQRS‐pre; 49%). However, it was masked in 35 (52% of fQRS‐pre) patients after the CRT. Inversely, in 70 patients in whom an fQRS was absent before the CRT, it appeared after the CRT in 15 (21%) patients. As a result, 47 patients (34%) had an fQRS after the CRT (fQRS‐post), and it was less than that before the CRT (P = 0.014). During 18 months of follow‐up, SCD or ventricular arrhythmic events were observed more frequently in patients with an fQRS‐post than in those without (36.2% vs. 3.3%, P < 0.001). A Cox regression analysis revealed that an fQRS‐post was significantly associated with those events (hazard ratio = 9.18; 95% confidence interval = 2.45–34.48, P = 0.001).

Conclusion

In patients with nonischemic cardiomyopathy who received CRT, an fQRS‐post was independently associated with SCD or ventricular arrhythmic events.
Role and regulation of p27 in neuronal apoptosis
Authors: Jaiswal Surbhi , Sharma Pushkar
Published: December 2016

It is necessary for the cell‐cycle machinery of neurons to be suppressed to promote differentiation and maintenance of their terminally differentiated state. Reactivation of the cell cycle in response to neurotoxic insults leads to neuronal cell death and some cell‐cycle‐related proteins contribute to the process. p27 kip1 (p27), an inhibitor of cyclin‐dependent kinases, prevents unwarranted cyclin‐dependent kinase activation. In this study, we have elucidated a novel mechanism via which p27 promotes apoptosis of neurons stimulated by neurotoxic amyloid peptide Aβ42 (Amyloid β1‐42 peptide). Co‐immunoprecipitation analysis revealed that p27 promotes interaction between Cyclin‐dependent kinase 5 (Cdk5) and cyclin D1, which is induced by Aβ42 in cortical neurons. As a result, Cdk5 is sequestered from its neuronal activator p35 resulting in kinase deactivation. The depletion of p27, which was achieved by specific siRNA, restored Cdk5/p35 interaction by preventing association between Cdk5 and cyclin D1 and also abrogated Aβ42 induced apoptosis of cortical neurons. Furthermore, analysis of cell cycle markers suggested that p27 may play a role in Aβ42 induced aberrant cell cycle progression of neurons, which may result in apoptosis. These findings provide novel insights into how p27, which otherwise performs important neuronal functions, may become deleterious to neurons under neurotoxic conditions.

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Transient receptor potential vanilloid type 4 channels mediate Na‐K‐Cl‐co‐transporter‐induced brain edema after traumatic brain injury
Authors: Lu Kwok‐Tung , Huang Tai‐Chun , Tsai Ya‐Hsin , Yang Yi‐Ling
Published: December 2016

Na+‐K+‐2Cl− co‐transporter (NKCC1) plays an important role in traumatic brain injury (TBI)‐induced brain edema via the MAPK cascade. The transient receptor potential vanilloid type 4 (TRPV4) channel participates in neurogenic inflammation, pain transmission, and edema. In this study, we investigated the relationship between NKCC1 and TRPV4 and the related signaling pathways in TBI‐induced brain edema and neuronal damage. TBI was induced by the calibrated weight‐drop device. Adult male Wistar rats were randomly assigned into sham and experimental groups for time‐course studies of TRPV4 expression after TBI. Hippocampal TRPV4, NKCC1, MAPK, and PI‐3K cascades were analyzed by western blot, and brain edema was also evaluated among the different groups. Expression of hippocampal TRPV4 peaked at 8 h after TBI, and phosphorylation of the MAPK cascade and Akt was significantly elevated. Administration of either the TRPV4 antagonist, RN1734, or NKCC1 antagonist, bumetanide, significantly attenuated TBI‐induced brain edema through decreasing the phosphorylation of MEK, ERK, and Akt proteins. Bumetanide injection inhibited TRPV4 expression, which suggests NKCC1 activation is critical to TRPV4 activation. Our results showed that hippocampal NKCC1 activation increased TRPV4 expression after TBI and then induced severe brain edema and neuronal damage through activation of the MAPK cascade and Akt‐related signaling pathway.

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DNA base excision repair proteins APE‐1 and XRCC‐1 are overexpressed in oral tongue squamous cell carcinoma
Authors: Santana Thalita , Sá Melka Coêlho , de Moura Santos Edilmar , Galvão Hébel Cavalcanti , Coletta Ricardo D. , Freitas Roseana de Almeida
Published: December 2016

Background

DNA repair systems play a critical role in protecting the human genome from damage caused by carcinogens. Modifications in DNA repair genes may be responsible for tumor development and resistance of malignant cells to chemotherapeutic agents. The major pathway for oxidative DNA damage repair is the base excision repair pathway. This study aimed to assess the immunoexpression of DNA repair proteins APE‐1 and XRCC‐1 and its association with clinical, histologic, and survival parameters in oral tongue squamous cell carcinoma, to investigate a possible role for those proteins in tumor behavior.

Methods

The expression of APE‐1 and XRCC‐1 was evaluated by immunohistochemistry in 82 cases of oral tongue squamous cell carcinoma. Histopathological grading was performed for each case. Pearson's chi‐square and Fisher's exact tests were used to determine the association between protein expressions and clinicopathological features of tumors, whereas Kaplan–Meier curves and Cox regression were used to analyze disease‐specific and disease‐free survival. Statistical significance was set at P ≤ 0.05.

Results

APE‐1 was highly expressed in the nucleus and cytoplasm in 64.6% of cases, and XRCC‐1 showed overexpression only in the nucleus in 61% of cases. High expression of XRCC‐1 was significantly associated with tumors at early clinical stages (I and II, P < 0.01) and nodal status (P = 0.03). Both proteins were not associated with other clinical parameters, histopathological grading, or survival.

Conclusions

DNA base excision repair proteins APE‐1 and XRCC‐1 are upregulated in oral tongue squamous cell carcinoma, and XRCC‐1 expression is associated with better clinical staging and nodal status.
NS5A inhibitors for the treatment of hepatitis C infection
Authors: Gitto Stefano , Gamal Nesrine , Andreone Pietro
Published: December 2016

Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct‐acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV‐NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response (SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance.
Hepatitis C viraemia reversibly maintains subset of antigen‐specific T‐bet+ tissue‐like memory B cells
Authors: Chang L.‐Y. , Li Y. , Kaplan D. E.
Published: December 2016

Background: Chronic antigen exposure and/or ageing increases the frequency of T‐box expressed in T cells (T‐bet)‐expressing B‐lymphocytes in mice. The frequency and significance of B‐cell T‐bet expression during chronic hepatitis C (HCV) infection in human subjects has never been described. Methods: Healthy controls, cirrhotic and noncirrhotic HCV‐infected patients, and non‐HCV patients with cirrhosis were recruited. Peripheral blood mononuclear cells were phenotyped for expression of T‐bet and related markers by flow cytometry. In a subset of patients who underwent antiviral therapy and were cured of HCV infection (sustained virological response), the dynamics of T‐bet expression in B cells was monitored. After cure, convalescent B cells were tested for T‐bet expression after re‐exposure to infected plasma or recombinant HCV proteins. Results: Forty‐nine patients including 11 healthy donors, 30 hepatitis C‐infected individuals (nine with liver cancer, 13 with cirrhosis, eight without cirrhosis) and eight patients with cirrhosis due to non‐HCV‐related cause were recruited. We found that B cells in patients with chronic HCV exhibited increased frequency of T‐bet+ B cells relative to noninfected individuals (median 11.5% v. 2.2%, P<.0001) but that there were no significant differences between noncirrhotic, cirrhotic and cancer‐bearing infected individuals. T‐Bet+ B cells expressed higher levels of CD95, CXCR3, CD11c, CD267 and FcRL5 compared to T‐bet− B cells and predominantly exhibit a tissue‐like memory CD27−CD21− phenotype independent of HCV infection. T‐bet+ B cells in HCV‐infected patients were more frequently class‐switched IgD−IgG+ (40.4% vs. 26.4%, P=.012). Resolution of HCV infection with direct‐acting antiviral (DAA) therapy leads to a marked reduction in the frequency of T‐bet+ B cells (median 14.1% pretreatment v. 6.7% end of treatment v. 6.1% SVR12, P≤.01). Re‐exposure of convalescent (cured) B cells to viremic plasma and recombinant HCV E2 protein led to re‐expression of T‐bet. Conclusion: Chronic antigenemia in chronic HCV infection induces and maintains an antigen‐specific T‐bet+ B cell. These B cells share markers with tissue‐like memory B cells. Antigen‐driven T‐bet expression may be a critical suppressor of B‐cell activation in chronic HCV infection.
Functional responses of contrasting seed predator guilds to masting in two Mediterranean oak species
Authors: Moreira Xoaquín , Pérez‐Ramos Ignacio M. , Abdala‐Roberts Luis , Mooney Kailen A.
Published: December 2016

The predator satiation hypothesis poses that synchronous and variable seed production during masting events increases seed escape through seed predator satiation. The success of this strategy depends upon the type of consumer functional response, in this case defined as the change in seed consumption rate by a predator as a function of change in seed density. Type II (where the proportion of seed consumed is highest at low levels of seed availability) and type III (where the proportion of seed consumed is highest at some intermediate level of seed availability and then declines towards zero) functional responses describe negative density‐dependence and indicate predator satiation. The type of function response should be contingent upon herbivore traits: type II responses are predicted for dietary specialist predators with low mobility, and type III responses are predicted for highly mobile, dietary generalist predators. Surprisingly, most studies have not evaluated whether functional responses vary among seed predator guilds. Here we describe the functional responses at population and individual tree level of highly mobile generalist (birds and rodents) and less mobile specialist (insects) pre‐dispersal seed predators attacking acorns of two sympatric oaks (Quercus suber and Q. canariensis) over a 10‐year period. Our results showed that in most cases specialist seed predators exhibited the predicted type II functional response at both the individual tree and population level for both oak species. However, generalist seed predators did not exhibit the predicted type III response; instead, they also exhibited a type II response at the individual tree and population level for both oak species. By independently assessing the effects of multiple seed predators associated with the same host tree species, our work highlights the influence of herbivore traits on the outcome of plant–seed predator interactions in masting species, and thus furthers our understanding of the ecological and evolutionary mechanisms underlying masting behaviour.
Transient severe tricuspid regurgitation after transplantation of an extremely oversized donor heart in a child—Does size matter? A case report
Authors: Birnbaum J. , Ulrich S. M. , Schramm R. , Hagl C. , Lehner A. , Fischer M. , Haas N. A. , Heineking B.
Published: December 2016

In pediatric heart transplantation, the size of the donor organ is an important criterion for organ allocation. Oversized donor hearts are often accepted with good results, but some complications in relation to a high donor‐recipient ratio have been described. Our patient was transplanted for progressive heart failure in dilated cardiomyopathy. The donor‐to‐recipient weight ratio was 3 (donor weight 65 kg, recipient weight 22 kg). The intra‐operative echocardiography before chest closure showed excellent cardiac function, no tricuspid valve regurgitation, and a normal central venous pressure. After chest closure, central venous pressure increased substantially and echocardiography revealed a severe tricuspid insufficiency. As other reasons for right ventricular dysfunction, that is, myocardial ischemia, pulmonary hypertension, and rejection, were excluded, we assumed that the insufficiency was caused by an alteration of the right ventricular geometry. After 1 week, the valve insufficiency regressed to a minimal degree. In pediatric heart transplant patients with a high donor‐to‐recipient weight ratio, the outlined complication may occur. If other reasons for right ventricular heart failure can be ruled out, this entity is most likely caused by an acute and transient alteration of the right ventricular geometry that may disappear over time.
Light Regulation of Alternative Pre‐mRNA Splicing in Plants
Authors: Zhang Hangxiao , Lin Chentao , Gu Lianfeng
Published: December 2016

Alternative splicing (AS) is a major post‐transcriptional mechanism to enhance the diversity of proteome in response to environmental signals. Among the numerous external signals perceived by plants, light is the most crucial one. Plants utilize complex photoreceptor signaling networks to sense different light conditions and adjust their growth and development accordingly. Although light‐mediated gene expression has been widely investigated, little is known regarding the mechanism of light affecting AS to modulate mRNA at the post‐transcriptional level. In this minireview, we summarize current progresses on how light affects AS, and how sensory photoreceptors and retrograde signaling pathways may coordinately regulate AS of pre‐mRNAs. In addition, we also discuss the possibility that AS of the mRNAs encoding photoreceptors may be involved in feedback control of AS. We hypothesize that light regulation of the expression and activity of splicing factors would be a major mechanism of light‐mediated AS. The combination of genetic study and high‐throughput analyses of AS and splicing complexes in response to light is likely to further advance our understanding of the molecular mechanisms underlying light control of AS and plant development.
A pupil size response model to assess fear learning
Authors: Korn Christoph W. , Staib Matthias , Tzovara Athina , Castegnetti Giuseppe , Bach Dominik R.
Published: December 2016

During fear conditioning, pupil size responses dissociate between conditioned stimuli that are contingently paired (CS+) with an aversive unconditioned stimulus, and those that are unpaired (CS‐). Current approaches to assess fear learning from pupil responses rely on ad hoc specifications. Here, we sought to develop a psychophysiological model (PsPM) in which pupil responses are characterized by response functions within the framework of a linear time‐invariant system. This PsPM can be written as a general linear model, which is inverted to yield amplitude estimates of the eliciting process in the central nervous system. We first characterized fear‐conditioned pupil size responses based on an experiment with auditory CS. PsPM‐based parameter estimates distinguished CS+/CS‐ better than, or on par with, two commonly used methods (peak scoring, area under the curve). We validated this PsPM in four independent experiments with auditory, visual, and somatosensory CS, as well as short (3.5 s) and medium (6 s) CS/US intervals. Overall, the new PsPM provided equal or decisively better differentiation of CS+/CS‐ than the two alternative methods and was never decisively worse. We further compared pupil responses with concurrently measured skin conductance and heart period responses. Finally, we used our previously developed luminance‐related pupil responses to infer the timing of the likely neural input into the pupillary system. Overall, we establish a new PsPM to assess fear conditioning based on pupil responses. The model has a potential to provide higher statistical sensitivity, can be applied to other conditioning paradigms in humans, and may be easily extended to nonhuman mammals.
Asymmetric Effects of Exchange Rate Changes and the J‐curve: New Evidence from 61 Malaysia–Thailand Industries
Authors: Bahmani‐Oskooee Mohsen , Aftab Muhammad
Published: December 2016

Research on the impact of currency depreciation on the trade balance is now moving in a new direction by incorporating nonlinear dynamic adjustment of the exchange rate and by using a nonlinear approach to error‐correction modeling and cointegration. Using these advances, researchers find not only more evidence of the J‐curve effect, but also new evidence of asymmetric effects of exchange rate changes on the trade balance. We contribute to this line of research by using monthly trade flow data from 61 two‐digit industries that trade between Malaysia and Thailand, and show that not only does currency depreciation have favorable effects on the trade balance of more industries, but the long‐run effects are asymmetric in 26 out of 61 cases. In line with current literature, our nonlinear model performs much better than the linear model when industry level data are used.
Job insecurity and discretionary behaviors: Social exchange perspective versus group value model
Authors: Piccoli Beatrice , De Witte Hans , Reisel William D.
Published: December 2016

This study examines the relationship between job insecurity and discretionary behaviors, that is, organizational citizenship behaviors (OCB) and counterproductive work behaviors (CWB), with the purpose to extend knowledge on the theoretical explanations for these outcomes. Considering the employment relationship with the organization, two different perspectives are suggested and compared in a multiple mediator model, in order to understand the reasons for discretionary behaviors. We draw upon social exchange theory as the basis of psychological contract perceptions and we rely on the group value model to explain organizational justice evaluations. A total of 570 blue‐collar workers in Italy participated in our survey. The results show that job insecurity is indirectly related to OCB and CWB through psychological contract breach and organizational injustice. Both mediational mechanisms have equivalent strength in explaining the relationships, namely, they are complementary processes in accounting for both behaviors. These findings suggest that employees’ behaviors in job insecure contexts are driven not only by concerns related to the exchange of resources with the organization, but also by evaluations about their value as important members of the group.
Effect of Phonetic Association on Learning Vocabulary in Foreign Language
Authors: Bozavlı Ebubekir
Published: December 2016

Word is one of the most important components of a natural language. Speech is meaningful because of the meanings of words. Vocabulary acquired in one’s mother tongue is learned consciously in a foreign language in non-native settings. Learning vocabulary in a system based on grammar is generally neglected or learned in conventional ways. This study is to determine the efficiency of teaching vocabulary from learning speed and retention perspective through means of phonetic association, whose examples are seldom seen in educational institutions. The study’s sample consists of Turkish 5th graders at three junior high school who have just begun to learn English. Sixty-six students, 37 girls and 29 boys from three socio-economically normal state schools. Thirty three students formed the experimental group while the other 33 students constituted the control group in the empirical study. “A phonetic association vocabulary test” consisting of 25 English words, mostly verbs and nouns, was designed. This test containing English words, their pronunciation and homophonous Turkish words was administered to the experimental group, knowing that vocabulary is taught by means of phonetic association. The control group was unaware of the method, and received the conventional teaching method. The control group was given a test containing only English words. The data obtained were decrypted by descriptive and content analysis. The study’s results revealed that words were learned faster and learning was retentive by the phonetic association method. In particular, recall of the words learned differentiates this method from conventional vocabulary learning methods.
Nonlocal Homogenization Model for Wave Dispersion and Attenuation in Elastic and Viscoelastic Periodic Layered Media
Authors: Hu Ruize , Oskay Caglar
Published: December 2016

This manuscript presents a new nonlocal homogenization model (NHM) for wave dispersion and attenuation in elastic and viscoelastic periodic layered media. Homogenization with multiple spatial scales based on asymptotic expansions of up to eighth order is employed to formulate the proposed nonlocal homogenization model. A momentum balance equation, nonlocal in both space and time, is formulated consistent with the gradient elasticity theory. A key contribution in this regard is that all model coefficients including high-order length-scale parameters are derived directly from microstructural material properties and geometry. The capability of the proposed model in capturing the characteristics of wave propagation in heterogeneous media is demonstrated in multiphase elastic and viscoelastic materials. The nonlocal homogenization model is shown to accurately predict wave dispersion and attenuation within the acoustic regime for both elastic and viscoelastic layered composites.
An Exploration Toward a Unified Failure Criterion
Authors: Xiao S. , Liu B.
Published: December 2016

For components with different defects, selecting a proper criterion to predict their failure is very important, but sometimes this brings confusion to engineers. In this paper, we explore to establish a unified failure criterion for defects with various geometries. First, a fundamental and universal law on failure that all criteria should follow, so-called the zeroth law of failure, is introduced, and the failure is completely governed by the local status of failure determining zone (FDZ), such as the stress distribution, material properties, and geometrical features. Failure criteria lacking a local dimension parameter within FDZ may have limited applicability, such as the traditional strength and fracture criteria. We choose the blunt V-notch as an example to demonstrate how to establish a unified failure criterion for quasi-brittle materials, and a series of experiments are carried out to verify its applicability. The proposed unified failure criterion and some existing failure criteria are also discussed and compared. The failure criteria that only include a single critical constant are incapable of reflecting the whole stress field information and local geometrical features of the FDZ. Our proposed unified failure criterion is expressed with a two-parameter function and has a wider applicability.
On the Two-Dimensional Simplification of Three-Dimensional Cementless Hip Stem Numerical Models
Authors: Quevedo González Fernando J. , Reimeringer Michael , Nuño Natalia
Published: December 2016

Three-dimensional (3D) finite element (FE) models are commonly used to analyze the mechanical behavior of the bone under different conditions (i.e., before and after arthroplasty). They can provide detailed information but they are numerically expensive and this limits their use in cases where large or numerous simulations are required. On the other hand, 2D models show less computational cost, but the precision of results depends on the approach used for the simplification. Two main questions arise: Are the 3D results adequately represented by a 2D section of the model? Which approach should be used to build a 2D model that provides reliable results compared to the 3D model? In this paper, we first evaluate if the stem symmetry plane used for generating the 2D models of bone-implant systems adequately represents the results of the full 3D model for stair climbing activity. Then, we explore three different approaches that have been used in the past for creating 2D models: (1) without side-plate (WOSP), (2) with variable thickness side-plate and constant cortical thickness (SPCT), and (3) with variable thickness side-plate and variable cortical thickness (SPVT). From the different approaches investigated, a 2D model including a side-plate best represents the results obtained with the full 3D model with much less computational cost. The side-plate needs to have variable thickness, while the cortical bone thickness can be kept constant.
Toward Medical Devices With Integrated Mechanisms, Sensors, and Actuators Via Printed-Circuit MEMS
Authors: Gafford Joshua , Ranzani Tommaso , Russo Sheila , Degirmenci Alperen , Kesner Samuel , Howe Robert , Wood Robert , Walsh Conor
Published: December 2016

Recent advances in medical robotics have initiated a transition from rigid serial manipulators to flexible or continuum robots capable of navigating to confined anatomy within the body. A desire for further procedure minimization is a key accelerator for the development of these flexible systems where the end goal is to provide access to the previously inaccessible anatomical workspaces and enable new minimally invasive surgical (MIS) procedures. While sophisticated navigation and control capabilities have been demonstrated for such systems, existing manufacturing approaches have limited the capabilities of millimeter-scale end-effectors for these flexible systems to date and, to achieve next generation highly functional end-effectors for surgical robots, advanced manufacturing approaches are required. We address this challenge by utilizing a disruptive 2D layer-by-layer precision fabrication process (inspired by printed circuit board manufacturing) that can create functional 3D mechanisms by folding 2D layers of materials which may be structural, flexible, adhesive, or conductive. Such an approach enables actuation, sensing, and circuitry to be directly integrated with the articulating features by selecting the appropriate materials during the layer-by-layer manufacturing process. To demonstrate the efficacy of this technology, we use it to fabricate three modular robotic components at the millimeter-scale: (1) sensors, (2) mechanisms, and (3) actuators. These modules could potentially be implemented into transendoscopic systems, enabling bilateral grasping, retraction and cutting, and could potentially mitigate challenging MIS interventions performed via endoscopy or flexible means. This research lays the ground work for new mechanism, sensor and actuation technologies that can be readily integrated via new millimeter-scale layer-by-layer manufacturing approaches.
Dynamics of Wave Propagation Across Solid–Fluid Movable Interface in Fluid–Structure Interaction
Authors: Kojima Tomohisa , Inaba Kazuaki , Takahashi Kosuke , Triawan Farid , Kishimoto Kikuo
Published: December 2016

A theoretical model for wave propagation across solid–fluid interfaces with fluid–structure interaction (FSI) was explored by conducting experiments. Although many studies have been conducted on solid–solid and fluid–fluid interfaces, the mechanism of wave propagation across solid–fluid interfaces has not been well examined. Consequently, our aim is to clarify the mechanism of wave propagation across a solid–fluid interface with the movement of the interface and develop a theoretical model to explain this phenomenon. In the experiments conducted, a free-falling steel projectile was used to impact a solid buffer placed immediately above the surface of water within a polycarbonate (PC) tube. Two different buffers (aluminum and polycarbonate) were used to examine the relation between wave propagation across the interface of the buffer and water and the interface movement. With the experimental results, we confirmed that the peak value of the interface pressure can be predicted via acoustic theory based on the assumption that projectile and buffer behave as an elastic body with local deformation by wave propagation. On the other hand, it was revealed that the average profile of the interface pressure can be predicted with the momentum conservation between the projectile and the buffer assumed to be rigid and momentum increase of fluid. The momentum transmitted to the fluid gradually increases as the wave propagates and causes a gradual decrease in the interface pressure. The amount of momentum was estimated via the wave speed in the fluid-filled tube by taking into account the coupling of the fluid and the tube.
Fault Diagnosis of Gearbox Using Particle Swarm Optimization and Second-Order Transient Analysis
Authors: Hussain Sajid
Published: December 2016

Detection of faults in a gearbox is a first and foremost step before diagnostic and prognostic operations are performed. This paper proposes a novel gearbox fault detection and feature extraction technique. The proposed method adaptively filters the vibration signals emanating from a gearbox. A bandpass filter is designed and optimized through particle swarm optimization (PSO) to maximize kurtosis as an objective function. Gearbox health-related features are extracted from the filtered signals using second-order transient analysis. The method is validated on experimental data collected from a running gearbox in healthy and faulty conditions. The proposed method has successfully identified the faulty conditions inside the gearbox.
Dynamic Response Analysis of Balance Drum Labyrinth Seal Groove Geometries Optimized for Minimum Leakage1
Authors: Untaroiu Alexandrina , Morgan Neal , Hayrapetian Vahe , Schiavello Bruno
Published: December 2016

Annular labyrinth seals often have a destabilizing effect on pump rotordynamics due to the large cross-coupled forces generated when the fluid is squeezed by an oscillating rotor. In this study, several novel groove geometries are investigated for their effect on the rotordynamic coefficients of the labyrinth seal. The groove cavity geometry of a baseline 267 mm balance drum labyrinth seal with a clearance of 0.305 mm and 20 equally spaced groove cavities was optimized for minimum leakage. From the pool of possible groove designs analyzed, nine test cases were selected for maximum or minimum leakage and for a variety of groove cavity shapes. The rotordynamic coefficients were calculated for these cases using a hybrid computational fluid dynamics (CFD) bulk-flow method. The rotordynamic coefficients obtained by this method were then used with a rotordynamic model of the entire pump to determine the overall stability. Results show that labyrinth seal’s groove shape can be optimized to generate lower leakage rates, while the effects on dynamic properties are only minimally changed. If the seal dynamic response needs to be modified in addition to targeting a lower leakage rate, for instance, to exhibit increased damping values, then the leakage rate and the damping coefficient need to be set as objective functions in the optimization loop.
Quasilinear reflection as a possible mechanism for suppressor-induced otoacoustic emission
Authors: Liu Yi-Wen , Liu Tzu-Chi
Published: December 2016

A frequency-domain iterative approach is developed to compute the change in characteristic impedance in the cochlea due to the presence of a suppressor tone. Based on this approach, a small transient wave passing by the best place (BP) of the suppressor is predicted to be partially reflected because of the suppressor-induced impedance variation. This computational approach is tested on a nonlinear model of cochlear mechanics [Liu, J. Acoust. Soc. Am. 136, 1788–1796 (2014)]. When a 9-kHz suppressor at 60 dB sound pressure level is delivered to the model, the characteristic impedance decreases by ∼20% near its BP. This localized impedance mismatch causes a forward-going wave at 4 kHz to reflect partially, and the magnitude of the reflected component is about –18 dB relative to the forward-going component near the stapes. The reflected components eventually emit from the cochlea to the ear canal, and the predicted amplitude of tone-burst evoked otoacoustic emissions (OAEs) agrees well with time-domain simulation. The present results suggest that, while the “suppressor” is meant to suppress the OAEs in experiments, its very presence might create an otherwise non-existing emission component via nonlinear scattering when its frequency is higher than that of the probe.
Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning
Authors: Azarov Ivan , Wang Ling , Rose Jason J. , Xu Qinzi , Huang Xueyin N. , Belanger Andrea , Wang Ying , Guo Lanping , Liu Chen , Ucer Kamil B. , McTiernan Charles F. , O’Donnell Christopher P. , Shiva Sruti , Tejero Jesús , Kim-Shapiro Daniel B. , Gladwin Mark T.
Published: December 2016

A mutant five-coordinate neuroglobin with a very high carbon monoxide binding affinity acts as an antidote to bind and eliminate CO.
Identification of Bicarbonate as a Trigger and Genes Involved with Extracellular DNA Export in Mycobacterial Biofilms
Authors: Rose Sasha J. , Bermudez Luiz E.
Published: December 2016

Extracellular DNA (eDNA) is an integral biofilm matrix component of numerous pathogens, including nontuberculous mycobacteria (NTM). Cell lysis is the source of eDNA in certain bacteria, but the source of eDNA remains unidentified for NTM, as well as for other eDNA-containing bacterial species. In this study, conditions affecting eDNA export were examined, and genes involved with the eDNA export mechanism were identified. After a method for monitoring eDNA in real time in undisturbed biofilms was established, different conditions affecting eDNA were investigated. Bicarbonate positively influenced eDNA export in a pH-independent manner in
Mycobacterium avium
,
M. abscessus
, and
M. chelonae
. The surface-exposed proteome of
M. avium
in eDNA-containing biofilms revealed abundant carbonic anhydrases. Chemical inhibition of carbonic anhydrases with ethoxzolamide significantly reduced eDNA export. An unbiased transposon mutant library screen for eDNA export in
M. avium
identified many severely eDNA-attenuated mutants, including one not expressing a unique FtsK/SpoIIIE-like DNA-transporting pore, two with inactivation of carbonic anhydrases, and nine with inactivation of genes belonging to a unique genomic region, as well as numerous mutants involved in metabolism and energy production. Complementation of nine mutants that included the FtsK/SpoIIIE and carbonic anhydrase significantly restored eDNA export. Interestingly, several attenuated eDNA mutants have mutations in genes encoding proteins that were found with the surface proteomics, and many more mutations are localized in operons potentially encoding surface proteins. Collectively, our data strengthen the evidence of eDNA export being an active mechanism that is activated by the bacterium responding to bicarbonate.

IMPORTANCE
Many bacteria contain extracellular DNA (eDNA) in their biofilm matrix, as it has various biological and physical functions. We recently reported that nontuberculous mycobacteria (NTM) can contain significant quantities of eDNA in their biofilms. In some bacteria, eDNA is derived from dead cells, but that does not appear to be the case for all eDNA-containing organisms, including NTM. In this study, we found that eDNA export in NTM is conditionally dependent on the molecules to which the bacteria are exposed and that bicarbonate positively influences eDNA export. We also identified genes and proteins important for eDNA export, which begins to piece together a description of a mechanism for eDNA. Better understanding of eDNA export can give new targets for the development of antivirulence drugs, which are attractive because resistance to classical antibiotics is currently a significant problem.
A Metabolic Widget Adjusts the Phosphoenolpyruvate-Dependent Fructose Influx in Pseudomonas putida
Authors: Chavarría Max , Goñi-Moreno Ángel , de Lorenzo Víctor , Nikel Pablo I.
Published: December 2016

The regulatory nodes that govern metabolic traffic in bacteria often show connectivities that could be deemed unnecessarily complex at a first glance. Being a soil dweller and plant colonizer,
Pseudomonas putida
frequently encounters fructose in the niches that it inhabits. As is the case with many other sugars, fructose is internalized by a dedicated phosphoenolpyruvate (PEP)-dependent transport system (PTS
Fru
), the expression of which is repressed by the fructose-1-P-responding Cra regulatory protein. However, Cra also controls a glyceraldehyde-3-P dehydrogenase that fosters accumulation of PEP (i.e., the metabolic fuel for PTS
Fru
). A simple model representing this metabolic and regulatory device revealed that such an unexpected connectivity allows cells to shift smoothly between fructose-rich and fructose-poor conditions. Therefore, although the metabolic networks that handle sugar (i.e., fructose) consumption look very similar in most eubacteria, the way in which their components are intertwined endows given microorganisms with emergent properties for meeting species-specific and niche-specific needs.
Cerebral tuberculomas in a patient with hairy cell leukaemia treated with cladribine
Authors: Fonseca Samuel Barbosa , de Oliveira Júlio Rodrigues , Gonçalves Cristina , Lopes Virgínia
Published: December 2016

A 67-year-old man was treated with cladribine for hairy cell leukaemia. A few weeks later, he presented with persistent headaches, intermittent hypoesthesia of the right upper limb and language impairment. Brain CT scan showed 3 contrast-enhancing lesions. MRI revealed infracentimetric nodular lesions with restricted diffusion. One of the lesions was surgically removed and tested positive for acid-fast bacilli. Moreover,Mycobacterium tuberculosiswas confirmed by PCR. Antituberculous drugs were prescribed for 12 months, with complete resolution of neurological deficits. This case highlights the risk of mycobacterial infections associated with both hairy cell leukaemia and cladribine use, and the importance of screening and treatment of latent forms of tuberculosis in patients undergoing treatment with immunosuppressive drugs.
Clarithromycin-induced akathisia: a class effect of macrolides?
Authors: Gbinigie Ivie Imasuen , Lasserson Daniel
Published: December 2016

Clarithromycin is an antibiotic of the macrolide family, which is commonly used in the treatment of respiratory tract infections. We report a woman aged 77 years with bronchiectasis who was prescribed oral clarithromycin for lower respiratory tract infection. She developed akathisia after 2 doses. On withdrawing the antibiotic, her symptoms resolved rapidly after 7 days.
Colorectal cancer mortality 10 years after a single round of guaiac faecal occult blood test (gFOBT) screening: experiences from a Danish screening cohort
Authors: Bjerrum Andreas , Andersen Ole , Fischer Anders , Lindebjerg Jan , Lynge Elsebeth
Published: December 2016

Background

In Denmark, colorectal cancer (CRC) is the third most frequent cancer. Randomised trials have shown that guaiac faecal occult blood test (gFOBT) screening can reduce CRC mortality, but a recent large randomised study from Finland did not find any effect. A feasibility study was carried out in Denmark in 2005–2006 where residents aged 50–74 years in 2 Danish counties were invited once to participate in gFOBT screening. We used the unique Danish registers to assess the impact of gFOBT screening in this group on CRC incidence and mortality.

Methods

In this cohort study, we followed a group comprising 166 277 individuals invited to screening and a reference group comprising the remaining 1 240 348 Danes of the same age. We linked the Danish population and health service registers to obtain information about colonoscopies, polypectomies, incident CRC and cause of death.

Results

After a median follow-up time of 8.9 years, the CRC mortality was significantly lower in the screening group than in the reference group with an adjusted HR (aHR) of 0.92 (95% CI 0.86 to 0.99), while the aHR for all-cause mortality was 0.95 (95% CI 0.94 to 0.96). For screening participants, the aHR for CRC mortality and all-cause mortality was 0.72 (0.64 to 0.80) and 0.59 (0.57 to 0.60), respectively.

Conclusions

About 10 years after a single round of gFOBT screening, we found a significant 8% deficit in CRC mortality in the screening group compared with other Danes. We found almost the same deficit in all-cause mortality, and on this basis, it is not possible to conclude that one screening round had an effect on CRC mortality. Our study indicated that close monitoring of the outcome of CRC screening is warranted.
Breast feeding initiation rate across Western countries: does religion matter? An ecological study
Authors: Bernard Jonathan Y , Cohen Emmanuel , Kramer Michael S
Published: December 2016

Background

Breast feeding initiation rates remain below 80% in some Western countries. Many individual-level determinants are known; however, less is known regarding cultural and societal determinants, such as religion, that could explain population-level variations. We examined the correlations of the proportions of Catholics and Protestants with the breast feeding initiation rates across and within Western countries.

Methods

Using publicly available data, we carried out an ecological study comparing the proportions of Catholics and Protestants with the rates of breast feeding initiation. We correlated data at the country level, and additionally explored within-country data in five Western countries: France (Departments), Ireland (counties), the UK (countries), Canada (provinces) and the USA (states). Our analyses accounted for human development index, gross domestic product and population density.

Results

We observed a negative correlation (r=−0.30) between the proportion of Catholics and the rate of breast feeding initiation in Western countries. This correlation was consistent when using within-country data in France (r=−0.27), Ireland (r=−0.23), the UK (r=−0.79) and Canada (r=−0.62). In the USA, the positive correlation (r=0.26) between a state's proportion of Catholics and its breast feeding initiation rate was confounded by race, education and socioeconomic status (SES). After controlling for education and SES, the state proportion of non-Hispanic white Catholics was negatively correlated (r=−0.29) with the rate of breast feeding initiation.

Conclusions

In this ecological study, we found consistent negative correlations between Catholicism and breast feeding initiation rates. Qualitative and quantitative studies at the individual level are needed to confirm and explain our findings. Our results suggest that women living in a country or region where Catholicism has historically dominated are less likely to initiate breast feeding, and that breast feeding promotion policies should be adapted to better fit populations' cultural and religious norms.