Παρασκευή, 5 Μαΐου 2017

In vitro and in vivo anti-uveal melanoma activity of JSL-1, a novel HDAC inhibitor

Publication date: 1 August 2017
Source:Cancer Letters, Volume 400
Author(s): Yun Wang, Maoxing Liu, Yanli Jin, Sheng Jiang, Jingxuan Pan
Uveal melanoma (UM) is the most common intraocular malignant neoplasm in adults. Despite the availability of enucleation, radiation and chemotherapy, the prognosis of patients with metastasis remains poor. Therefore, novel effective therapies for patients with metastatic UM are urgently needed. In the present study, we demonstrated that JSL-1, a novel HDAC inhibitor, effectively inhibited the proliferation. JSL-1 induced apoptosis with increased expression of proapoptotic BH3-only protein BIM in UM cells. JSL-1 suppressed migration and invasion of UM cells with MMP-2 decreased. Furthermore, JSL-1 blocked the canonical Wnt/β-catenin pathway, impaired self-renewal capacity and decreased percentage of ALDH+ cells, thereby reflecting elimination of UM cancer stem-like cells (CSCs) which are believed seeds of metastasis. Importantly, JSL-1 potently inhibited the growth of uveal melanoma xenograft in NOD-SCID mice. These results suggested that JSL-1 may be a promising therapeutic agent for UM.



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Editorial Board

Publication date: 10 July 2017
Source:Cancer Letters, Volume 398





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Rates of inappropriate laboratory test utilization in Ontario

Publication date: Available online 5 May 2017
Source:Clinical Biochemistry
Author(s): Nadine Chami, Janet Simons, Arthur Sweetman, Andrew C. Don Wauchope
BackgroundMedical laboratory tests ordered redundantly represent one of the targets for reducing diagnostic testing without negatively, and possibly positively, affecting patient care. We study a clearly defined category of excessive laboratory utilization for nine analytes where inappropriate diagnostic testing is defined in terms of the time interval between tests; that is, ordering a test too soon following the previous order of the same test.MethodsPopulation data from the near universal public Ontario Health Insurance Plan for the years 2006–2010 are employed where the tests are fulfilled by community medical laboratories. The analytes selected for consideration are thyroid stimulating hormone, hemoglobin A1c, lipid profile, serum protein electrophoresis, immunofixation, quantitative immunoglobulins, Vitamin D, Vitamin B12, and folate.ResultsFor the nine analytes studied, the percentage of inappropriate tests ranged from 6% to 20%. Large proportions of these inappropriate tests were completed >2weeks prior to the minimum threshold to reorder defined by practice guidelines and/or were repeated excessively within a year. Between 60% and 85% of the time, the ordering physician of an inappropriate test was the same physician who ordered the previous test. Specialists were more likely than primary care physicians to order repeat tests too soon.ConclusionsA sizeable proportion of testing for these analytes was inappropriate according to practice guidelines. It is recommended that systems for preventing unnecessary repeat testing are investigated by the funding agencies and that reducing inappropriate testing be considered as a design element for electronic medical records and related information technology systems.



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Evaluation of diagnostic accuracy of two rapid stool antigen tests using an immunochromatographic assay to detect Helicobacter pylori

Publication date: Available online 5 May 2017
Source:Clinical Biochemistry
Author(s): Joyce Matie Kinoshita da Silva-Etto, Rejane Mattar, Cibele Aparecida Villares-Lopes, Sergio Barbosa Marques, Flair José Carrilho
ObjectivesThe stool antigen assay for H. pylori infection diagnosis with monoclonal antibodies is a simple and recommended technique by the Maastricht V/Florence consensus report. Recently, Pylori K-Set K-1219 (Coris Bioconcept Sprl, Belgium) and HP-F23 (Symbiosys, Brazil) have been made commercially available in Brazil. Thus, the aim of this study was to evaluate the diagnostic accuracies of these two rapid stool antigen tests by immunochromatographic assays (index tests) for the clinical practice.Design and methodsA total of 98 patients who underwent upper gastrointestinal endoscopy and 13C-urea breath test entered the study. H. pylori infection status was defined by the combination of the rapid urease test and the 13C-urea breath test (reference standard). Two observers who were aware of H. pylori status performed the reading of index tests. Diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value with 95% confidence intervals, positive likelihood ratio, negative likelihood ratio and kappa index measure of agreement) were determined.ResultsThe index tests where in perfect agreement with the H. pylori status with kappa values of 0.87 for Pylori K-Set K-1219 and 0.92 for HP-F23. The sensitivity of HP-F23 was 97.9% (IC95%: 87.5–100) and specificity was 93.8% (IC95%; 84–97.2).The positive likelihood ratio was 15.8, and the negative likelihood ratio was 0.02. The Pylori K-Set K-1219 had a sensitivity of 87.7% (IC95%: 74.5–94.9) and a specificity of 100% (IC95%: 91.6–100); the positive likelihood ratio was ∞, and the negative likelihood ratio was 0.1. The test line on the cassette device of HP-F23 was stronger than of the Pylori K-Set K-1219.ConclusionThe HP-F23 test performed better in clinical practice. Nonetheless, the 13C-urea breath test is more reliable technique. Moreover, caution must be paid to the trace or clear pale test line readings that were observed in false positive and false negative results, leading to incorrect management of the patient.



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Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration

Publication date: July 2017
Source:Free Radical Biology and Medicine, Volume 108
Author(s): Cátia F. Lourenço, Ana Ledo, Rui M. Barbosa, João Laranjinha
The strict energetic demands of the brain require that nutrient supply and usage be fine-tuned in accordance with the specific temporal and spatial patterns of ever-changing levels of neuronal activity. This is achieved by adjusting local cerebral blood flow (CBF) as a function of activity level – neurovascular coupling – and by changing how energy substrates are metabolized and shuttled amongst astrocytes and neurons – neuroenergetic coupling. Both activity-dependent increase of CBF and O2 and glucose utilization by active neural cells are inextricably linked, establishing a functional metabolic axis in the brain, the neurovascular-neuroenergetic coupling axis. This axis incorporates and links previously independent processes that need to be coordinated in the normal brain. We here review evidence supporting the role of neuronal-derived nitric oxide (NO) as the master regulator of this axis. Nitric oxide is produced in tight association with glutamatergic activation and, diffusing several cell diameters, may interact with different molecular targets within each cell type. Hemeproteins such as soluble guanylate cyclase, cytochrome c oxidase and hemoglobin, with which NO reacts at relatively fast rates, are but a few of the key in determinants of the regulatory role of NO in the neurovascular-neuroenergetic coupling axis. Accordingly, critical literature supporting this concept is discussed. Moreover, in view of the controversy regarding the regulation of catabolism of different neural cells, we further discuss key aspects of the pathways through which NO specifically up-regulates glycolysis in astrocytes, supporting lactate shuttling to neurons for oxidative breakdown. From a biomedical viewpoint, derailment of neurovascular-neuroenergetic axis is precociously linked to aberrant brain aging, cognitive impairment and neurodegeneration. Thus, we summarize current knowledge of how both neurovascular and neuroenergetic coupling are compromised in aging, traumatic brain injury, epilepsy and age-associated neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, suggesting that a shift in cellular redox balance may contribute to divert NO bioactivity from regulation to dysfunction.

Graphical abstract

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Twist buckling of veins under torsional loading

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Justin R. Garcia, Arnav Sanyal, Fatemeh Fatemifar, Mohammad Mottahedi, Hai-Chao Han
Veins are often subjected to torsion and twisted veins can hinder and disrupt normal blood flow but their mechanical behavior under torsion is poorly understood. The objective of this study was to investigate the twist deformation and buckling behavior of veins under torsion. Twist buckling tests was performed on porcine internal jugular veins (IJVs) and human great saphenous veins (GSVs) at various axial stretch ratio and lumen pressure conditions to determine their critical buckling torques and critical buckling twist angles. The mechanical behavior under torsion was characterized using a two-fiber strain energy density function and the buckling behavior was then simulated using finite element analysis. Our results demonstrated that twist buckling occurred in all veins under excessive torque characterized by a sudden kink formation. The critical buckling torque increased significantly with increasing lumen pressure for both porcine IJV and human GSV. But lumen pressure and axial stretch had little effect on the critical twist angle. The human GSVs are stiffer than the porcine IJVs. Finite element simulations captured the buckling behavior for individual veins under simultaneous extension, inflation, and torsion with strong correlation between predicted critical buckling torques and experimental data (R2=0.96). We conclude that veins can buckle under torsion loading and the lumen pressure significantly affects the critical buckling torque. These results improve our understanding of vein twist behavior and help identify key factors associated in the formation of twisted veins.



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The implication of the osteolysis threshold and interfacial gaps on periprosthetic osteolysis in cementless total hip replacement

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Hamidreza Alidousti, Neil W. Bressloff
Osteolysis around joint replacements may develop due to migration of wear particles from the joint space into gaps between the interface bone and the implant where they can accumulate in high concentrations to cause tissue damage. Osteolysis may appear in various postoperative times and morphological shapes which can be generalized into linear and focal. However, there are no clear explanations on the causes of such variations. Patients’ degree of sensitivity to polyethylene particles (osteolysis thresholds), the local particle concentration and the access route provided by the interface gaps have been described as determining factors. To study their effects, a 2D computational fluid dynamics model of the hip joint capsule in communication with an interfacial gap and the surrounding bone was employed. Particles were presented using a discrete phase model (DPM). High capsular fluid pressure was considered as the driving force for particle migration. Simulations were run for different osteolysis thresholds ranging from 5 ×108 to 1 ×1012 particle number per gram of tissue and fibrous tissue generation in osteolytic lesion due to particles was simulated for the equivalent of ten postoperative years. In patients less sensative to polyethylene particles (higher threshold), osteolysis may be linear and occur along an interfacial gap in less than 5% of the interfatial tissue. Focal osteolysis is more likely to develop in patients with higher sensitivity to polyethylene particles at distal regions to an interfacial gaps where up to 80% of the interfatial tissue may be replaced by fibrous tissue. In these patients, signs of osteolysis may also develop earlier (third postoperative year) than those with less sensitivity who may show very minor signs even after ten years. This study shows the importance of patient sensitivity to wear particles, the role of interfatial gaps in relation to morphology and the onset of osteolysis. Consequently, it may explain the clinically observed variation in osteolysis development.



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Connecting the wrist to the hand: a simulation study exploring changes in thumb-tip endpoint force following wrist surgery

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Jennifer A. Nichols, Michael S. Bednar, Sarah J. Wohlman, Wendy M. Murray
The wrist is essential for hand function. Yet, due to the complexity of the wrist and hand, studies often examine their biomechanical features in isolation. This approach is insufficient for understanding links between orthopaedic surgery at the wrist and concomitant functional impairments at the hand. We hypothesize that clinical reports of reduced force production by the hand following wrist surgeries can be explained by the surgically-induced, biomechanical changes to the system, even when those changes are isolated to the wrist. This study develops dynamic simulations of lateral pinch force following two common surgeries for wrist osteoarthritis: scaphoid-excision four-corner fusion (SE4CF) and proximal row carpectomy (PRC). Simulations of lateral pinch force production in the nonimpaired, SE4CF, and PRC conditions were developed by adapting published models of the nonimpaired wrist and thumb. Our simulations and biomechanical analyses demonstrate how the increased torque-generating requirements at the wrist imposed by the orthopaedic surgeries influence force production to such an extent that changes in motor control strategy are required to generate well-directed thumb-tip end-point forces. The novel implications of our work include identifying the need for surgeries that optimize the configuration of wrist axes of rotation, rehabilitation strategies that improve post-operative wrist strength, and scientific evaluation of motor control strategies following surgery. Our simulations of SE4CF and PRC replicate surgically-imposed decreases in pinch strength, and also identify the wrist’s torque-generating capacity and the adaptability of muscle coordination patterns as key research areas to improve post-operative hand function.



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Supra-annular Valve-in-Valve Implantation Reduces Blood Stasis on the Transcatheter Aortic Valve Leaflets

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Koohyar Vahidkhah, Ali N. Azadani
Leaflet thrombosis following transcatheter aortic valve replacement (TAVR) and Valve-in-Valve (ViV) procedures has been increasingly recognized. This study aimed to investigate the effect of positioning of the transcatheter aortic valve (TAV) in ViV setting on the flow dynamics aspect of post-ViV thrombosis by quantifying the blood stasis in the intra-annular and supra-annular settings. To that end, two idealized computational models, representing ViV intra-annular and supra-annular positioning of a TAV were developed in a patient-specific geometry. Three-dimensional flow fields were then obtained via fluid-solid interaction modeling to study the difference in blood residence time (BRT) on the TAV leaflets in the two settings. At the end of diastole, a strip of high BRT (⩾1.2s) region was observed on the TAV leaflets in the ViV intra-annular positioning at the fixed boundary where the leaflets are attached to the frame. Such a high BRT region was absent on the TAV leaflets in the supra-annular positioning. The maximum value of BRT on the surface of non-, right, and left coronary leaflets of the TAV in the supra-annular positioning were 53%, 11%, and 27% smaller compared to the intra-annular positioning, respectively. It was concluded that the geometric confinement of TAV by the leaflets of the failed bioprosthetic valve in ViV intra-annular positioning increases the BRT on the leaflets and may act as a permissive factor in valvular thrombosis. The absence of such a geometric confinement in the ViV supra-annular positioning leads to smaller BRT and subsequently less likelihood of leaflet thrombosis.



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Validation of the AnyBody full body musculoskeletal model in computing lumbar spine loads at L4L5 level

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Tito Bassani, Elena Stucovitz, Zhihui Qian, Matteo Briguglio, Fabio Galbusera
In the panorama of available musculoskeletal modeling software, AnyBody software is a commercial tool that provides a full body musculoskeletal model which is increasingly exploited by numerous researchers worldwide. In this regard, model validation becomes essential to guarantee the suitability of the model in representing the simulated system. When focusing on lumbar spine, the previous works aimed at validating the AnyBody model in computing the intervertebral loads held several limitations, and a comprehensive validation is to be considered as lacking.The present study was aimed at extensively validating the suitability of the AnyBody model in computing lumbar spine loads at L4L5 level. The intersegmental loads were calculated during twelve specific exercise tasks designed to accurately replicate the conditions during which Wilke at al. (2001) measured in vivo the L4L5 intradiscal pressure. Motion capture data of one volunteer subject were acquired during the execution of the tasks and then imported into AnyBody to set model kinematics. Two different approaches in computing intradiscal pressure from the intersegmental load were evaluated. Lumbopelvic rhythm was compared with reference in vivo measurements to assess the accuracy of the lumbopelvic kinematics.Positive agreement was confirmed between the calculated pressures and the in vivo measurements, thus demonstrating the suitability of the AnyBody model. Specific caution needs to be taken only when considering postures characterized by large lateral displacements. Minor discrepancy was found assessing lumbopelvic rhythm. The present findings promote the AnyBody model as an appropriate tool to non-invasively evaluate the lumbar loads at L4L5 in physiological activities.



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Quantitative assessment of trunk deformation during running

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Shoma Kudo, Masahiro Fujimoto, Tadao Isaka, Akinori Nagano
The trunk has a multi-segmental structure and is composed of the cervical, thoracic, and lumber spines and surrounding soft tissue elements; this allows flexible deformation during dynamic movements. The purpose of this study was to quantitatively assess trunk deformation during dynamic movement. Ten male subjects performed running at four different speeds: 8 km/h, 10 km/h, 12 km/h, and 14 km/h. Forty reflective markers were placed on the backs of these individuals to define 56 small triangular areas, and three-dimensional kinematic data was recorded with a motion capture system. The coefficients of variation (CV) of the horizontal and vertical lengths between two adjacent markers and the standard deviation (SD) of the normal vectors of triangular areas were calculated as measures for translational and angular trunk deformation, respectively. Up to about 14% of CV and 78 degrees of SD appeared as the measure of translational and angular deformation, respectively. These results imply that the trunk underwent a significant amount of position-specific deformation. These findings would be useful in the construction of an optimal trunk segment model to represent the complex and flexible trunk movement during dynamic movements.



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Measurement of peak impact loads differ between accelerometers – effects of system operating range and sampling rate

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Christina Ziebart, Lora M. Giangregorio, Jenna Gibbs, Iris C. Levine, James Tung, Andrew Laing
A wide variety of accelerometer systems, with differing sensor characteristics, are used to detect impact loading during physical activities. The study examined the effects of system characteristics on measured peak impact loading during a variety of activities by comparing outputs from three separate accelerometer systems, and by assessing the influence of simulated reductions in operating range and sampling rate. Twelve healthy young adults performed seven tasks (vertical jump, box drop, heel drop, and bilateral single leg and lateral jumps) while simultaneously wearing three tri-axial accelerometers including a criterion standard laboratory-grade unit (Endevco 7267A) and two systems primarily used for activity-monitoring (ActiGraph GT3X+, GCDC X6-2mini). Peak acceleration (gmax) was compared across accelerometers, and errors resulting from down-sampling (from 640 to 100 Hz) and range-limiting (to ±6g) the criterion standard output were characterized. The Actigraph activity-monitoring accelerometer underestimated gmax by an average of 30.2%; underestimation by the X6-2mini was not significant. Underestimation error was greater for tasks with greater impact magnitudes. gmax was underestimated when the criterion standard signal was down-sampled (by an average of 11%), range limited (by 11%), and by combined down-sampling and range-limiting (by 18%). These effects explained 89% of the variance in gmax error for the Actigraph system. This study illustrates that both the type and intensity of activity should be considered when selecting an accelerometer for characterizing impact events. In addition, caution may be warranted when comparing impact magnitudes from studies that use different accelerometers, and when comparing accelerometer outputs to osteogenic impact thresholds proposed in literature.



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Computational Study to Investigate Effect of Tonometer Geometry and Patient-Specific Variability on Radial Artery Tonometry

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Pranjal Singh, Mohammed Ikbal Choudhury, Sitikantha Roy, Anamika Prasad
Tonometry-based devices are valuable method for vascular function assessment and for measurement of blood pressure. However current design and calibration methods rely on simple models, neglecting key geometrical features, and anthropometric and property variability among patients. Understanding impact of these influences on tonometer measurement is thus essential for improving outcomes of current devices, and for proposing improved design. Towards this goal, we present a realistic computational model for tissue-device interaction using complete wrist section with hyperelastic material and frictional contact. Three different tonometry geometries were considered including a new design, and patient-specific influences incorporated via anthropometric and age- dependent tissue stiffness variations. The results indicated that the new design showed stable surface contact stress with minimum influence of the parameters analyzed. The computational predictions were validated with experimental data from a prototype based on the new design. Finally, we showed that the underlying mechanics of vascular unloading in tonometry to be fundamentally different from that of oscillatory method. Due to directional loading in tonometry, pulse amplitude maxima was observed to occur at a significantly lower compression level (around 31%) than previously reported, which can impact blood pressure calibration approaches based on maximum pulse pressure recordings.



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An augmented iterative method for identifying a stress-free reference configuration in image-based biomechanical modeling

Publication date: Available online 5 May 2017
Source:Journal of Biomechanics
Author(s): Manuel K. Rausch, Martin Genet, Jay D. Humphrey
Continued advances in computational power and methods have enabled image-based biomechanical modeling to become an important tool in basic science, diagnostic and therapeutic medicine, and medical device design. One of the many challenges of this approach, however, is identification of a stress-free reference configuration based on in vivo images of loaded and often prestrained or residually stressed soft tissues and organs. Fortunately, iterative methods have been proposed to solve this inverse problem, among them Sellier’s method. This method is particularly appealing because it is easy to implement, convergences reasonably fast, and can be coupled to nearly any finite element package. By means of several practical examples, however, we demonstrate that in its original formulation Sellier’s method is not optimally fast and may not converge for problems with large deformations. Fortunately, we can also show that a simple, inexpensive augmentation of Sellier’s method based on Aitken’s delta-squared process can not only ensure convergence but also significantly accelerate the method.



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Osgood-Schlatter disease

Osgood-Schlatter disease: A condition involving inflammation and sometimes tearing of ligaments within the knee and lower leg. Treatment is by rest, casting if necessary, and sometimes surgery.

Osgood-Schlatter disease is caused by repetitive stress or tension on a part of the growth area of the upper tibia (the apophysis). It is characterized by inflammation of the patellar tendon and surrounding soft tissues at the point where the tendon attaches to the tibia. The disease may also be associated with an avulsion injury, in which the tendon is stretched so much that it tears away from the tibia and takes a fragment of bone with it. The disease most commonly affects active young people, particularly boys between the ages of 10 and 15, who play games or sports that include frequent running and jumping.

People with this disease experience pain just below the knee joint that usually worsens with activity and is relieved by rest. A bony bump that is particularly painful when pressed may appear on the upper edge of the tibia (below the knee cap). Usually, motion of the knee is not affected. Pain may last a few months and may recur until a child's growth is completed.

Osgood Schlatter disease is most often diagnosed by the symptoms. An x ray may be normal, or show an avulsion injury, or, more typically, show that the apophysis is in fragments.

The disease usually disappears without treatment. Applying ice to the knee when pain first begins helps relieve inflammation and is sometimes used along with stretching and strengthening exercises. The doctor may advise the patient to limit participation in vigorous sports. Children who wish to continue participating in moderate or less stressful sports may need to wear knee pads for protection and apply ice to the knee after activity. If a great deal of pain is felt during sports activities, participation may be limited until any remaining discomfort is tolerable.



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Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors

Publication date: August 2017
Source:Cellular Signalling, Volume 36
Author(s): Susanne Prokop, Nicole A. Perry, Sergey A. Vishnivetskiy, Andras D. Toth, Asuka Inoue, Graeme Milligan, Tina M. Iverson, Laszlo Hunyady, Vsevolod V. Gurevich
Non-visual arrestins interact with hundreds of different G protein-coupled receptors (GPCRs). Here we show that by introducing mutations into elements that directly bind receptors, the specificity of arrestin-3 can be altered. Several mutations in the two parts of the central “crest” of the arrestin molecule, middle-loop and C-loop, enhanced or reduced arrestin-3 interactions with several GPCRs in receptor subtype and functional state-specific manner. For example, the Lys139Ile substitution in the middle-loop dramatically enhanced the binding to inactive M2 muscarinic receptor, so that agonist activation of the M2 did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M2, whereas its interactions with other receptors, including the β2-adrenergic receptor and the D1 and D2 dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the β2-adrenergic and D2 dopamine receptors, while reducing its interaction with the D1 dopamine receptor. These mutations represent the first example of altering arrestin specificity via enhancement of the arrestin-receptor interactions rather than selective reduction of the binding to certain subtypes.



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Crystal structure of tissue factor in complex with antibody 10H10 reveals the signaling epitope

Publication date: Available online 5 May 2017
Source:Cellular Signalling
Author(s): Alexey Teplyakov, Galina Obmolova, Thomas J. Malia, Bingyuan Wu, Yonghong Zhao, Susann Taudte, G. Mark Anderson, Gary L. Gilliland
Tissue factor (TF) initiates the extrinsic pathway of blood coagulation through sequential binding and activation of coagulation factors VII (FVII) and X (FX). In addition, through activation of G-protein-coupled protease activated receptors (PARs) TF induces cell signaling that is related to cancer, angiogenesis and inflammation. Monoclonal antibodies (mAbs) proved to be a useful tool for studying the interplay between TF signaling and coagulation. MAb 10H10 is unique in that it blocks the signaling pathway and thus inhibits angiogenesis and tumor growth without interfering with coagulation. It was also presumed that mAb 10H10 recognizes the cryptic pool of TF devoid of procoagulant activity. The crystal structure of the 10H10 Fab was determined in the absence and in the presence of the TF extracellular domain (ECD). The structures show that the antibody operates by the key-and-lock mechanism causing no conformational changes in either Fab or TF. The TF:10H10 interface is extensive and includes five segments of TF in both the N-terminal and C-terminal domains of the ECD. Neither the known epitope of FVII, nor the putative epitope of FX overlaps with the 10H10 binding site. The 10H10 epitope points to the likely location of the PAR2 exosite. It is also the hypothetical site of TF interaction with integrins that may play a major role in the encryption-decryption process.

Graphical abstract

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Protein mediated regulation of the NHE1 isoform of the Na+/H+ exchanger in renal cells. A regulatory role of Hsp90 and AKT kinase

Publication date: Available online 5 May 2017
Source:Cellular Signalling
Author(s): Ayodeji Odunewu-Aderibigbe, Larry Fliegel
Na+/H+ exchanger isoform one (NHE1) is a pH regulatory protein that is present in renal tissues and serves to remove protons from within cells and protect against intracellular acidification. NHE1 has a large 315 amino acid cytosolic regulatory domain that regulates the catalytic membrane domain. We examined protein-mediated regulation of NHE1 through the cytosolic domain. Affinity chromatography with the C-terminus of NHE1 yielded a number of NHE1 binding proteins including 14-3-3 protein, heat shock proteins (Hsp90 and Hsp70) and Na+/K+ ATPase. We confirmed that 14-3-3 and heat shock proteins bind to or regulate NHE1 but could not confirm that Na+/K+ ATPase binds to the intact protein. The Hsp90 inhibitor 17-AAG decreased NHE1 activity and NHE1 phosphorylation in MDCK cells but did not decrease protein levels. Additionally, 17-AAG decreased phospho-AKT levels. Direct inhibition of AKT with MK2206 decreased NHE1 activity, though this effect was not additive with the effect of 17-AAG. The results demonstrate that in renal cells, NHE1 is associated with several regulatory proteins including Hsp90, and that Hsp90 affects its function possibly through altered phosphorylation of the protein via the AKT kinase.



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Off-pump CABG in chronic lymphocytic leukaemia: case report and review

Abstract

Coronary artery disease (CAD) was uncommonly seen in people with haematological malignancies in the past. Such cases are routinely encountered now due to increased survival of these patients. Surgical intervention for CAD in such cases in not without risk and hence a technique with minimal operative risk should be employed. Additional risks due to cardiopulmonary bypass (CPB) may be minimized using the off-pump technique which has been reported to be favourable in recent literature. We have reviewed the existing literature of off-pump CABG in CLL and report here a case of use of such technique with good outcome.



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Can classification performance be predicted by complexity measures? A study using microarray data

Abstract

Data complexity analysis enables an understanding of whether classification performance could be affected, not by algorithm limitations, but by intrinsic data characteristics. Microarray datasets based on high numbers of gene expressions combined with small sample sizes represent a particular challenge for machine learning researchers. This type of data also has other particularities that may negatively affect the generalization capacity of classifiers, such as overlaps between classes and class imbalance. Making use of several complexity measures, we analyzed the intrinsic complexity of several microarray datasets with and without feature selection and then explored the connection with the empirical results obtained by four widely used classifiers. Experimental results for 21 binary and multiclass datasets demonstrate that a correlation exists between microarray data complexity and the classification error rates.



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Editorial Board



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Sex differences in avoidance behavior after perceiving potential risk in mice

Sex has been considered as a potential factor regulating individual behaviors in different contexts. Recently, findings on sex differences in the neuroendocrine circuit have expanded due to exact measurements ...

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The Effects of Three Physical and Vocal Warm-Up Procedures on Acoustic and Perceptual Measures of Choral Sound

The purpose of this investigation was to assess the effects of three warm-up procedures (vocal-only, physical-only, physical/vocal combination) on acoustic and perceptual measures of choir sound.

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Rebound thrombocytosis and persistence of clinical symptoms after recovery from dengue hemorrhagic fever

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Won Sriwijitralai, Viroj Wiwanitkit

Annals of Tropical Medicine and Public Health 2017 10(1):286-286



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Myopericytom

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Sunil Y Swami, Harshiya Gupta, Grace D'Costa

Annals of Tropical Medicine and Public Health 2017 10(1):261-263



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Elements dictating the fate of artemisinin combination therapy in India

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Dipanjan Bhattacharjee, G Shiva Prakash, Thomson Rose Sereen

Annals of Tropical Medicine and Public Health 2017 10(1):7-12

Over the course of its existence in India, Artemisinin combination therapy (ACT), has emerged as the titular tool at mankind's disposal to counter falciparum malaria related mortalities. The dramatic slide in reported deaths due to Plasmodium falciparum is a testament to ACT's efficacy. However, a closer look reveals the successes so far achieved with ACT to be only a smokescreen. A large majority of the patients in the more remote and backward regions of India, still remain bereft of ACT, which might be the reason for the startling malaria mortality figures reported by the community surveillances. In our manuscript, we have laid focus on the key facets of the Indian health care system that has purportedly played a central role in the present successes with ACT. Further, we have highlighted as to how these key elements, for instance, health workers like Accredited Social Health Activists (ASHAs), sub-centers, supply chain of ACT can be improved upon further so as to ensure that ACT is able to reach the truly needy.

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Ten lessons learned from the recent outbreak of the Middle East respiratory syndrome

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Ali Mehrabi Tavana

Annals of Tropical Medicine and Public Health 2017 10(1):231-233

From 2012 till the present, the name of Middle East respiratory syndrome (MERS) has been heard many a times in the mass media and many papers that have been published in different scientific journals, but one question has remained – What is the lesson learned about MERS epidemic at the present time and what can really be done in order to prevent the matter? I would like to bring your attention to what could be done at the present time, based on lessons learned from MERS outbreak in the world.

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Sand fly fever: An important vector-borne diseases for travelers?

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Ali Mehrabi Tavana

Annals of Tropical Medicine and Public Health 2017 10(1):13-15

Context: Sand fly fever is a vector-borne viral infection and is endemic in many parts of the world, particularly in areas that are infected with different types of leishmaniasis. Clinical spectrum ranges from asymptomatic infection to very high fever and photophobia in patients. During the last decades, an increase in imported sand fly fever cases in developed and nonendemic countries have been pointed out from an international literature review. Among the possible causes are increasing international travelers, travel of immigrants from endemic area, and army operations. It has been noted that the main region for the diseases are west of Asia and east of Europe, and perhaps imported cases may be seen clinically in different parts of the world, either in developed or in developing countries. Materials and Methods: Two methods were used to gather the information for this article. First, PubMed was searched for English language references to published relevant articles. Second, the term sand fly fever was searched on Google Scholar too. Results: In PubMed, 156 articles and in Google Scholar, 70,400 articles mentioned the term sand fly fever. The most searched items in PubMed were epidemiology, treatment, prevention, and life cycle with incidences of 41.66, 20.51, 13.46, and 1.92%, respectively, and in terms of geographical distribution of the study, the maximum number of articles in PubMed were published from Europe, Asia, Australia, and America, with percentages being 26.92, 17.30, 17.0, 1.28, and 1.28%, respectively. Conclusion: Different countries have reported the disease either as an endemic or as an imported one. co-infection. Sand fly fever must be considered in the diagnostic assessment of patients presenting with a similar clinical syndrome and a history of travel to an endemic area, which are mentioned above. Adventure travelers, researchers, military personnel, and other groups of travelers likely to be exposed to sand flies in endemic areas; these travelers should receive counseling regarding sand fly fever appropriate protective health measures. In this review article sand fly fever situation will be studied.

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Improving patient safety standards in hospitals: A global public health concern

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Saurabh R Shrivastava, Prateek S Shrivastava, Jegadeesh Ramasamy

Annals of Tropical Medicine and Public Health 2017 10(1):275-276



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Interventions for improved retention of skilled health workers in rural and remote areas

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Manas Ranjan Behera, Chardsumon Prutipinyo, Nithat Sirichotiratana, Chukiat Viwatwongkasem

Annals of Tropical Medicine and Public Health 2017 10(1):16-21

Background: Worldwide, rural inequitable distribution and dearth of health professionals pose poor functioning of health services. In this study, we gather interventions aimed at increasing the proportion of health professionals working in rural and remote areas. Methods: We searched PUBMED, MEDLINE, EMBASE and google scholar database with key words such as “doctors”, “nurses” “health workers”, “health care professionals” and “human resources for health”. Further, comprehensive data base of relevant literature on recruitment or retention or both, of health workers in rural and remote areas has been searched through the websites of different government, non-government, national and international agencies. Results: We found that, there are mainly four interventions employed for improved rural retention. These interventions are generally grouped into educational, financial, regulatory, personal and professional strategies. We also judged the effectiveness of the intervention provided in the literature. Conclusion: Currently, there is limited reliable evidence regarding the effects of these interventions aimed at addressing the maldistribution of health professionals. Hence, well-designed observational studies are needed to confirm that educational, financial, regulatory, personal and professional strategies might influence the health workers' decision to stay in underserved areas. Further, the state governments, public health schools and medical colleges should ensure that when interventions are implemented, their impacts can be measured through scientifically rigorous approaches to establish the true effects of these measures for improved rural recruitment and retention.

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Prospects of mandibular advancement device (MAD) as a preferred treatment of obstructive sleep apnea in India: a systematic review

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Abhishek Dubey, Surya Kant, Darshan Kumar Bajaj, Balendra Pratap Singh

Annals of Tropical Medicine and Public Health 2017 10(1):1-6

Obstructive sleep apnea (OSA) is an independent risk factor for increased cardiovascular and cerebro-vascular morbidity and mortality. OSA leads to loss of human life and huge economical burden to our Society worldwide. The adult's prevalence of OSA ranges between 9.3-13.5% in India. India is the second largest populated country of the world and by the end of 2030 it may become the most populated nation. This developing nation is already known as the world's capital of T2 DM, and other non-communicable diseases like Obesity, Hypertension, Stroke, Ischemic heart diseases (IHD), Hypercholesterolemia congestive heart failure are on a rising trend. These cardiovascular disorders were found to be associated with OSA. OSA treatment may improve these co-morbid conditions. Continuous positive airway pressure (CPAP) is a preferred choice for OSA treatment in western and developed countries. In India, where CPAP is out of the reach of most of the OSA affected population due to high cost and other socio-economic and cultural factors, MAD may become a preferred treatment option. MAD is cheaper than CPAP and generally equally effective. The patients suffering from sleep-related breathing disorder (SBD) may have an alternative to CPAP or surgery for their disease management. Mandibular Advancement Device (MAD) may become an additional standard treatment of OSA in India, and has great potential for reducing associated undesirable cardiovascular co-morbidities and mortalities. This review highlights the prospects of MAD as a preferred treatment of Obstructive Sleep Apnea in India by extensively researching scientific literature, PubMed, Google Scholar, scientific, and academic web portals.

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Spectrum of physical deformities in leprosy patients visiting a tertiary care center in Mangalore

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A Kashinath Nayak, Radhika Satheesh, Kotian Shashidhar

Annals of Tropical Medicine and Public Health 2017 10(1):22-26

Background: Presence of physical deformities in patients with leprosy reflects the rate of disease transmission in the community; delay in detection of cases; and inadequacy or failure of treatment. Objectives: To determine the spectrum of physical deformities in patients with leprosy, to analyze the various sociodemographic factors affecting the study population, and to assess the treatment history of the selected number of patients. Materials and Methods: The study was an analytical study conducted on all leprosy patients who visited the dermatology out-patient department in a tertiary care hospital during the period of 1 year. Results: Males constituted 70.66% and females constituted 29.34%. It was found that a majority were in the age group of 21–60 years than in the extreme age groups (0–20 years and 61–80 years). Among the 92 patients studied, it was found that majority of the patients (60.86%) had WHO grade 0 or grade 1 deformity. Those with visible deformities (WHO grade 2 deformity) constituted 39.13% of the study population. Among those with visible deformities, the most common deformity was seen to be trophic ulcer (21.73%). This was followed by claw hand, foot drop, madarosis, claw toes, lagophthalmos, ear lobe deformity, facial palsy, and finally nose deformity. Conclusions: Our study found that more than one third of number of leprosy patients had deformities. It reflects the need for further efforts to curb this infectious disease and increase education among masses.

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Intestinal amebiasis presenting as life threatening lower GI bleed-A rare presentation

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VK Dogra, D Gupta, R Kashyap, Laxmi Nand, Sachin Sondhi

Annals of Tropical Medicine and Public Health 2017 10(1):244-246

Amoebiasis is a common intestinal protozoan infection due to Entamoeba histolytica. In India, the prevalence of the disease varies from 2% to 67%.[1] Acute Fulminant Colitis is a rare complication of intestinal amebiasis. Life threatening lower Gastrointestinal bleed is very rare presentation of amebiasis. Here, we are presenting a case of severe lower GI bleed proved to be caused by amebiasis along with extra intestinal complications.

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Mobile phone dependence among undergraduate medical students in Nanded city

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Vijay K Domple, Satish K Wadde, PL Gattani

Annals of Tropical Medicine and Public Health 2017 10(1):27-30

Introduction: In recent years, there has been increasing concern regarding problematic use of mobile phones, and accordingly, it has been publicized extensively as an emerging social problem. Objective: The aim of the study was to assess mobile phone dependence among undergraduate medical students of the Nanded city. Material and Methods: A cross-sectional study was conducted among undergraduate medical students of a Government Medical college, Nanded, Maharashtra, during November to December 2016. All the 348 students in the college were enrolled in the study. A predesigned Test of Mobile Phone Dependence (TMD Brief) developed by Chóliz et al was used for collection of information. The participants scoring ≥ 50%, that is, a score of ≥ 30 were considered as mobile dependent. Data analysis was performed using SPSS Version 20 and Graph Pad Prism. Results: Out of 348 participants, data were collected from 251 students, and 206 (82.1%) students were found to be dependent on the mobile phone. In total, 137 (85.1%) students in the age group of 17–20 years were mobile phone dependent. Most of the mobile phone dependents were females 99 (83.9%) than males, that is, 107 (80.5%). Out of 206 mobile-phone-dependent students, majority 77 (90.6%) were from the first year. The chi square test showed that the mobile phone dependence was significantly dependent on the academic year (X2=6.82, P=0.033). The binary logistic regression also proved first year as an independent risk factor for mobile dependence compared to second and third years. Conclusions: A total of 82.1% undergraduate medical students were mobile phone dependent. Health education about the use of mobile phone is necessary in the first year.

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Vector-borne diseases quiz for MD students

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Sagar Atmaram Borker

Annals of Tropical Medicine and Public Health 2017 10(1):267-272



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Indoor air quality at shopping malls in Kota Kinabalu, Sabah (particulate matter and ozone)

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Carolyn Payus, Carmen Chai

Annals of Tropical Medicine and Public Health 2017 10(1):31-35

Background: Indoor air quality (IAQ) in shopping malls is an interesting case of study since a shopping mall is a public place where people favor to spend their time. This study was conducted to investigate the IAQ of shopping malls in Kota Kinabalu, Sabah, whereby three shopping malls were selected as investigation sites. Methods: The parameters being studied include particulate matter (PM0.3-∞, PM0.5-∞, PM2-∞ and PM5-∞) and ozone. Indoor and outdoor air measurements were performed in the three shopping malls on weekdays and weekends to determine the I/O ratios. Results: In this study, overall average indoor PM concentrations on weekends were higher than weekdays, reaching maxima average concentrations of 421.44 ± 102.96 µg/m3 for PM0.3-∞, 41.75 ± 15.54 µg/m3 for PM0.5-∞, 1.30 ± 0.41 µg/m3 for PM2-∞, and 0.21 ± 0.09 µg/m3 for PM5-∞. Correlation between indoor and outdoor PM concentrations mostly showed poor relationship in the three shopping malls, showing that indoor sources such as re-suspension phenomena due to occupant's activities were clearly the main contributors to indoor PM concentrations. Poor ventilation system also affected IAQ by increasing the PM accumulation. However, I/O ratios were often less than 1.0, indicating that PM in indoor air arises predominantly from outdoor air transported to indoors. Average indoor ozone concentration at all the shopping malls was measured to be below the 0.05 ppm of ICOP-IAQ 2010. Conclusion: The overall assessment of IAQ in the three shopping malls showed that SM2 has a better IAQ compared to SM1 and SM3.

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Supporting and encouraging breastfeeding through strengthening of the existing legal provisions globally

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Saurabh RamBihariLal Shrivastava, Prateek Saurabh Shrivastava, Jegadeesh Ramasamy

Annals of Tropical Medicine and Public Health 2017 10(1):280-282



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Evaluate the decision of as low as reasonably practicable (ALARP) solutions for the safe use of pesticide among the pesticide handlers, paddy farm, Tanjung Karang, Selangor

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Vivien How, Khaval Abdullah, Khairuddin Bin Othman

Annals of Tropical Medicine and Public Health 2017 10(1):36-43

Introduction: Most of the farmers encounter the similar problems such as low-financial capacity and lack of information to control over the pesticide hazards. This study highlights the importance of the approach of As Low As Reasonably Practicable (ALARP) solutions to control and reduce the identified health risks from the pesticide use. Objective: To evaluate the decision of ALARP solutions for the safe use of pesticide among the pesticide handlers. Methodology: This cross-sectional study was conducted among 85 pesticide handlers to evaluate the ALARP practical solutions. The solution shall consider the factors that could control and mitigate the health risks suitably and cost-effectively. Result and Discussion: Pesticide handlers were aware of the fact that using hazardous pesticides without appropriate control equipment is detrimental to their health. When ALARP solutions are considered, respondents prefer to utilize the control strategies that are less likely to incur costs. Among all, the practices of the safe system of work and administrative control are highly recommended to mitigate the potential health risks during mixing and loading, application, and drift control and decontamination. Conclusion: It is recommended to apply the ALARP solutions to control and mitigate the pesticide risks sustainable during mixing and loading, application, drift reduction and decontamination.

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Maternal and neonatal tetanus elimination accomplished from the south-east Asian Region: World Health Organization

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Saurabh R Shrivastava, Prateek S Shrivastava, Jegadeesh Ramasamy

Annals of Tropical Medicine and Public Health 2017 10(1):289-290



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A case crossover analysis of primary air pollutants association on acute respiratory infection (ARI) among children in urban region of Klang valley, Malaysia

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SR Abdul Rahman, S. N. S Ismail, M Sahani, Mohammad Firuz Ramli, Mohammad Talib Latif

Annals of Tropical Medicine and Public Health 2017 10(1):44-55

Introduction: Acute respiratory infection (ARI) among children is one of the health effects associated with poor air quality. Objective: This study explores the distribution of ARI cases by subtypes among children in an urban region in tropical country and its association with the air pollution level. Method: Secondary data of primary air pollutants and the ARI data recorded at the selected main public hospital in the same area from 2006 to 2010 were analyzed descriptively using statistical software and spatially through the geographical information system (GIS). Results: In total, 54,542 cases of ARI hospital admission among children were reported with 16 subtypes. Most of the ARI cases were recorded at the general hospital located in the city center (Kuala Lumpur Hospital, N = 27,719, 50.82%), and other cases were distributed at the hospitals located at suburbs (Serdang Hospital, N = 6868 (12.59%), Selayang Hospital, N = 6548, (12.01%), and Klang Hospital, N = 5434, (9.96%). Most of the patients were boys (N = 31,682, 58.09%) and aged below 5 years (N = 45,393, 83.22%). Thirteen ARI subtypes were influenced by the particulate matter with diameter size less than 10 µm (PM10), followed by NO2 (eight subtypes), CO (four sub-types), and O3 (two sub-types). PM10 contributes to high risk of acute bronchiolitis (odd ratio (OR): 1.115, 95% CI: 1.093-1.138), acute upper respiratory infection of multiple and unspecified sites (OR: 1.065, 95% CI: 1.034-1.096), and unspecified acute lower respiratory infection (OR: 1.055, 95% CI: 1.051–1.059). In conclusion, this study supported the theory that children were mainly exposed to air pollution in urban area and they were at risk to experience ARI.

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A study on the blood feeding behavior of sand flies on ABO blood groups using PCR methods in Southeastern Iran

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Fasihi Harandi Majid, Aghaei Afshar Abbas, Hamidreza Mollaie, Kamran Akbarzadeh

Annals of Tropical Medicine and Public Health 2017 10(1):222-227

Objective: Cutaneous leishmaniasis (CL) is presently occurring in Kerman province, southeastern Iran. The objective of this study was to determine the correlation between the different blood groups and the blood feeding behavior of sand flies. Materials and Methods: Sticky paper traps were used to collect sand flies in the study location. Traps were set at dusk and flies were collected at dawn. A total of 200-300 sticky traps were set each day in each area. Results: A total of 1320 sandflies were collected; 320 blood-fed female sandflies were selected for the analysis of blood meals by PCR-RFLP. In this study, 82 (25.6%) sandflies fed on human blood meals. Conclusion: The results of the current study clearly indicated that there is a significant relationship between the different blood groups and the blood feeding behavior of sand flies.

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Heavy metals contamination in eye shadows sold in Malaysia and user's potential health risks

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Jacquline Sue Jac Lim, Yu Bin Ho, Hazwanee Hamsan

Annals of Tropical Medicine and Public Health 2017 10(1):56-64

Background: Nowadays, eye shadows have become common cosmetics used by consumers. Previous studies proved that some of the eye shadows used had excessive levels of heavy metals. Objectives: The aims of this study are to (i) quantify the heavy metals concentration of lead and chromium in the eye shadows based on the color categories and types of eye shadows and (ii) assess potential non-carcinogenic health risk due exposure to heavy metals concentrations in eye shadows by using Hazard Quotient (HQ). Methodology: A conventional method using oven heating was applied to extract heavy metals from the samples. The analysis of heavy metals in the samples was performed using the Graphite Furnace Atomic Absorption Spectrophotometer (GF-AAS). The chronic non-carcinogenic health effect was evaluated quantitatively using HQ. Results: Both lead and chromium concentrations were found to be the highest in blue color category with the mean concentration of 161.8 ± 101.6 µg kg−1 and 149.4 ± 53.1 µg kg−1, respectively. The chromium levels were higher in the shimmering shade compared to the matte shade. The lead concentrations in all the samples analyzed were below the standard set by Health Canada (10 mg kg−1) and United States Food and Drug Administration (20 mg kg−1). The HQ values for chromium in all samples were less than 1. Conclusion: Lead concentrations were present within the permitted levels stated by the international standards in cosmetics intended for external use. The HQ values for chromium were less than 1 in all samples, indicating there was no significant chronic non-carcinogenic health risk to eye shadow users.

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Symmetric peripheral gangrene: A rare complication of Plasmodium falciparum malaria

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Sunita Kumbhalkar, Archana Aher, Shashank Wanjari

Annals of Tropical Medicine and Public Health 2017 10(1):238-240

Sudden onset of symmetric peripheral gangrene (SPG) is a relatively uncommon clinical entity manifested by distal ischemic damage at two or more sites in the absence of large vessel obstruction. Here, we report a case of a 27-year-old female with complicated falciparum malaria with SPG involving the toes of both the lower limbs.

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Altered cargo proteins of human plasma endothelial cell-derived exosomes in atherosclerotic cerebrovascular disease [Research]

Plasma endothelial cell–derived exosomes (EDEs) and platelet-derived exosomes (PDEs) were precipitated and enriched separately by immunospecific absorption procedures for analyses of cargo proteins relevant to atherosclerosis. EDEs had usual exosome size and marker protein content, and significantly higher levels than PDEs of the endothelial proteins vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase, whereas PDEs had significantly higher levels of platelet glycoprotein VI. EDE levels of VCAM-1, von Willebrand factor, platelet-derived growth factor (PDGF)-BB, angiopoietin-1, and lysyl oxidase-2 and the cerebrovascular-selective proteins glucose transporter 1, permeability-glycoprotein, and large neutral amino acid transporter 1 were significantly higher for 18 patients with cerebrovascular disease (CeVD) than for 18 age- and gender-matched control subjects. PDE levels of PDGF-AA, platelet glycoprotein VI, integrin-linked kinase-1, high mobility group box-1 protein, chemokine CXCL4, and thrombospondin-1 were significantly higher in patients with CeVD than in control subjects, but differences were less with greater overlaps than for EDE proteins. EDE levels of Yes-associated protein (YAP) were higher and of P(S127)-YAP lower in patients with CeVD than in control subjects, consistent with heightened activity of this mechanical force–sensitive system in atherosclerosis. Elevated EDE and PDE levels of atherosclerosis-promoting proteins in CeVD justify clinical studies of their potential value as biomarkers.—Goetzl, E. J., Schwartz, J. B., Mustapic, M., Lobach, I. V., Daneman, R., Abner, E. L., Jicha, G. A. Altered cargo proteins of human plasma endothelial cell–derived exosomes in atherosclerotic cerebrovascular disease.



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A sustained increase of plasma fibrinogen in sudden sensorineural hearing loss predicts worse outcome independently

A number of etiologies of idiopathic sudden sensorineural hearing loss (ISSNHL) have been proposed. Vascular disturbance is one cause of ISSNHL and has been reported to be associated with fibrinogen. We aimed to determine whether hyperfibrinogenemia is associated with poor outcome and whether a serial change in fibrinogen level is associated with outcome.

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Decreased clinic visits for acute respiratory infections following an adult tonsillectomy: A population-based study

This study attempted to investigate the effects of a tonsillectomy on utilization of medical resources for acute respiratory infections by comparing numbers and costs of clinic visits within 1year before and after a tonsillectomy.

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Retrograde Parotidectomy and facial nerve outcomes: A case series of 44 patients

The most common surgical method to remove benign parotid tumors remains the prograde approach. We examined if a retrograde surgical technique offers better outcomes than historical prograde controls.

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MicroRNA-1301 Suppresses Tumor Cell Migration and Invasion by Targeting the p53/UBE4B Pathway in Multiple Human Cancer Cells

The p53 protein plays a critical role in preventing tumor development. Although numerous factors have been shown to directly or indirectly regulate p53, the mechanism of how microRNAs (miRNAs) modulate p53 remains unclear. Here, we identified miR-1301, a microRNA that regulates the activity and function of p53, by directly targeting the ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase. Notably, ectopic expression of miR-1301 inhibits dissemination and metastasis of tumor cells in a p53-dependent manner.

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Thioredoxin-1 Promotes Colorectal Cancer Invasion and Metastasis through Crosstalk with S100P

Thioredoxin-1 (Trx-1) is a small redox-regulating protein, which plays an important role in several cellular functions. Despite recent advances in understanding the biology of Trx-1, the role of Trx-1 and its underlying signaling mechanism in colorectal cancer (CRC) metastasis have not been extensively studied. In this study, we observed that Trx-1 expression is increased in CRC tissues compared to the paired non-cancerous tissues and is significantly correlated with clinical staging, lymph node metastasis and poor survival.

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Clinical characteristics of patients with low functional IL-6 production upon TLR/IL-1R stimulation

Low IL-6 production upon stimulation by TLR/IL-1R ligands is associated with increased susceptibility to bacterial skin infections and to invasive infections with P. aeruginosa and/or with a IRAK-4/MyD88/NEMO defect.

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Characterization of liver metastasis and its impact on targeted therapy in EGFR mutant NSCLC: A multicenter study

The risk factors of liver metastasis (LM) in patients with non-small-cell lung cancer (NSCLC) remain unknown. Whether LM predicts the effect of first-line EGFR-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant NSCLC needs to be explored.

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Second-Generation Drosophila Chemical Tags: Sensitivity, Versatility, and Speed

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Ben Sutcliffe<br />Apr 1, 2017; 205:1399-1408<br />Methods, technology and resources

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Genomic Rearrangements in Arabidopsis Considered as Quantitative Traits

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Martha Imprialou<br />Apr 1, 2017; 205:1425-1441<br />Statistical Genetics and Genomics

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Inference of Gene Flow in the Process of Speciation: An Efficient Maximum-Likelihood Method for the Isolation-with-Initial-Migration Model

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Rui J. Costa<br />Apr 1, 2017; 205:1597-1618<br />Population and evolutionary genetics

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Mobile Introns Shape the Genetic Diversity of Their Host Genes

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Jelena Repar<br />Apr 1, 2017; 205:1641-1648<br />Population and evolutionary genetics

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Circadian Rhythms and Sleep in Drosophila melanogaster

Christine Dubowy<br />Apr 1, 2017; 205:1373-1397<br />Nervous System and Behaviour

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A Bayesian Approach for Analysis of Whole-Genome Bisulfite Sequencing Data Identifies Disease-Associated Changes in DNA Methylation

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Owen J. L. Rackham<br />Apr 1, 2017; 205:1443-1458<br />Statistical Genetics and Genomics

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Wheat Landrace Genome Diversity

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Luzie U. Wingen<br />Apr 1, 2017; 205:1657-1676<br />Genetics of complex traits

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Soft Selective Sweeps in Evolutionary Rescue

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Benjamin A. Wilson<br />Apr 1, 2017; 205:1573-1586<br />Population and evolutionary genetics

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Toothpicks, Serendipity and the Emergence of the Escherichia coli DnaK (Hsp70) and GroEL (Hsp60) Chaperone Machines

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Costa Georgopoulos<br />Dec 1, 2006; 174:1699-1707<br />PERSPECTIVES

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Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency

The Bacillus Calmette-Guérin (BCG) preparations are live-attenuated derivatives of Mycobacterium bovis. These products are used to vaccinate infants at birth, a practice that may result in a disseminated infectio...

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Th9 Cells



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Structural insights into the molecular function of human [2Fe-2S] BOLA1-GRX5 and [2Fe-2S] BOLA3-GRX5 complexes

Publication date: Available online 5 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Veronica Nasta, Andrea Giachetti, Simone Ciofi-Baffoni, Lucia Banci
Members of the monothiol glutaredoxin family and members of the BolA-like protein family have recently emerged as specific interacting partners involved in iron-sulfur protein maturation and redox regulation pathways. It is known that human mitochondrial BOLA1 and BOLA3 form [2Fe-2S] cluster-bridged dimeric heterocomplexes with the monothiol glutaredoxin GRX5. The structure and cluster coordination of the two [2Fe-2S] heterocomplexes as well as their molecular function are, however, not defined yet. Experimentally-driven structural models of the two [2Fe-2S] cluster-bridged dimeric heterocomplexes, the relative stability of the two complexes and the redox properties of the [2Fe-2S] cluster bound to these complexes are here presented on the basis of UV/vis, CD, EPR and NMR spectroscopy and computational protein-protein docking. While the BOLA1-GRX5 complex coordinates a reduced, Rieske-type [2Fe-2S]+ cluster, an oxidized, ferredoxin-like [2Fe-2S]2+ cluster is present in the BOLA3-GRX5 complex. The [2Fe-2S] BOLA1-GRX5 complex is preferentially formed over the [2Fe-2S] GRX5-BOLA3 complex, as a result of a higher cluster binding affinity. All these observed differences provide the first indications discriminating the molecular function of the two [2Fe-2S] heterocomplexes.

Graphical abstract

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Selectivity of major isoquinoline alkaloids from Chelidomium majus towards telomeric G-quadruplex: A study using a modified transition-FRET (t-FRET) assay

Publication date: Available online 4 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Sakineh Kazemi Noureini, Hosein Esmaeili, Farzane Abachi, Soraia Khiali, Barira Islam, Martyna Kuta, Ali A. Saboury, Marcin Hoffmann, Jiri Sponer, Gary Parkinson, Shozeb Haider
BackgroundNatural bioproducts are invaluable resources in drug discovery. Isoquinoline alkaloids of Chelidonium majus constitute a structurally diverse family of natural products that are of great interest, one of them being their selectivity for human telomeric G-quadruplex structure and telomerase inhibition.MethodsThe study focuses on the mechanism of telomerase inhibition by stabilization of telomeric G-quadruplex structures by berberine, chelerythrine, chelidonine, sanguinarine and papaverine. Telomerase activity and mRNA levels of hTERT were estimated using quantitative telomere repeat amplification protocol and qPCR, in MCF-7 cells treated with different groups of alkaloids. The selectivity of the main isoquinoline alkaloids of Chelidonium majus towards telomeric G-quadruplex forming sequences were explored using a sensitive modified thermal FRET-melting measurement in the presence of the complementary oligonucleotide CT22. We assessed and monitored G-quadruplex topologies using circular dichroism (CD) methods, and compared spectra to previously well-characterized motifs, either alone or in the presence of the alkaloids, Molecular modeling was performed to rationalize ligand binding to the G-quadruplex structure.ResultsThe results highlight strong inhibitory effects of chelerythrine, sanguinarine and berberine on telomerase activity, most likely through substrate sequestration. These isoquinoline alkaloids interacted strongly with telomeric sequence G-quadruplex. In comparison, chelidonine and papaverine had no significant interaction with the telomeric quadruplex, while they strongly inhibited telomerase at transcription level of hTERT. Altogether, all of the studied alkaloids showed various levels and mechanisms of telomerase inhibition.ConclusionsWe report on a comparative study of anti-telomerase activity of the isoquinoline alkaloids of Chelidonium majus. Chelerythrine was most effective in inhibiting telomerase activity by substrate sequesteration through G-quadruplex stabilization.General SignificanceUnderstanding structural and molecular mechanisms of anti-cancer agents can help in developing new and more potent drugs with fewer side effects. Isoquinolines are the most biologically active agents from Chelidonium majus, which have shown to be telomeric G-quadruplex stabilizers and potent telomerase inhibitors.



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Tipping the balance of RNA stability by 3’ editing of the transcriptome

Publication date: Available online 5 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Christina Z. Chung, Lauren E. Seidl, Mitchell R. Mann, Ilka U. Heinemann
BackgroundThe regulation of active microRNAs and maturation of messenger RNAs that are competent for translation is a crucial point in the control of all cellular processes, with established roles in development and differentiation. Terminal nucleotidyltransferases (TNTases) are potent regulators of RNA metabolism. TNTases promote the addition of single or multiple nucleotides to an RNA transcript that can rapidly alter transcript stability. The well-known polyadenylation promotes transcript stability while the newly discovered but ubiquitious 3’ end polyuridylation marks RNA for degradation. Monoadenylation and uridylation are essential control mechanisms balancing mRNA and miRNA homeostasis.Scope of ReviewThis review discusses the multiple functions of non-canonical TNTases, focusing on their substrate range, biological functions, and evolution. TNTases directly control mRNA and miRNA levels, with diverse roles in transcriptome stabilization, maturation, silencing, or degradation. We will summarize the current state of knowledge on non-canonical nucleotidyltransferases and their function in regulating miRNA and mRNA metabolism. We will review the discovery of uridylation as an RNA degradation pathway and discuss the evolution of nucleotidyltransferases along with their use in RNA labeling and future applications as therapeutic targets.Major ConclusionsThe biochemically and evolutionarily highly related adenylyl- and uridylyltransferases play antagonizing roles in the cell. In general, RNA adenylation promotes stability, while uridylation marks RNA for degradation. Uridylyltransferases evolved from adenylyltransferases in multiple independent evolutionary events by the insertion of a histidine residue into the active site, altering nucleotide, but not RNA specificity.General SignificanceUnderstanding the mechanisms regulating RNA stability in the cell and controlling the transcriptome is essential for efforts aiming to influence cellular fate. Selectively enhancing or reducing RNA stability allows for alterations in the transcriptome, proteome, and downstream cellular processes. Genetic, biochemical and clinical data suggest TNTases are potent targets for chemotherapeutics and have been exploited for RNA labeling applications.



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Erratum: Antidiabetic Activities of an LC/MS Fingerprinted Aqueous Extract of Fagonia cretica L. in Preclinical Models

Planta Med
DOI: 10.1055/s-0043-109620



Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text



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Small teams of myosin Vc motors coordinate their stepping for efficient cargo transport on actin bundles [Molecular Biophysics]

Myosin Vc (myoVc) is unique among vertebrate class V myosin isoforms in that it requires teams of motors to move continuously on single actin filaments. Single molecules of myoVc cannot take multiple hand-over-hand steps from one actin binding site to the next without dissociating, in stark contrast to the well-studied myosin Va (myoVa) isoform. At low salt, single myoVc motors can, however, move processively on actin bundles, and at physiologic ionic strength, even teams of myoVc motors require actin bundles to sustain continuous motion. Here, we linked defined numbers of myoVc or myoVa molecules to DNA nanostructures as synthetic cargos. Using TIRF microscopy, we compared the stepping behavior of myoVc versus myoVa ensembles, and myoVc stepping patterns on single actin filaments versus actin bundles. Run lengths of both myoVc and myoVa teams increased with motor number, but only multiple myoVc motors showed a run length enhancement on actin bundles compared with actin filaments. By resolving the stepping behavior of individual myoVc motors with a quantum dot bound to the motor domain, we found that coupling of two myoVc motors significantly decreased the futile back and side steps that were frequently observed for single myoVc motors. Changes in the inter-motor distance between two coupled myoVc motors affected stepping dynamics, suggesting that mechanical tension coordinates the stepping behavior of two myoVc motors for efficient directional motion. Our study provides a molecular basis to explain how teams of myoVc motors are suited to transport cargos such as zymogen granules on actin bundles.

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Enhancing the Domain Wall Conductivity in Lithium Niobate Single Crystals

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01199
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Glycol Chitosan Engineered Autoregenerative Antioxidant Significantly Attenuates Pathological Damages in Models of Age-Related Macular Degeneration

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b00429
ancac3?d=yIl2AUoC8zA


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All Fox News All The Time on FDA Headquarters TV?

Agency claims channels rotate, but some workers say that is no longer true

-- Read more on ScientificAmerican.com
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Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study

Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II...

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Diaphragmatic Surgery and Related Complications In Primary Cytoreduction for Advanced Ovarian, Tubal, and Peritoneal Carcinoma

To evaluate the procedures and complications of diaphragm peritonectomy (DP) and diaphragm full-thickness resection (DFTR) during primary cytoreduction for advanced stage epithelial ovarian cancer.

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Interval breast cancer characteristics before, during and after the transition from screen-film to full-field digital screening mammography

To determine the proportion of “true” interval cancers and tumor characteristics of interval breast cancers prior to, during and after the transition from screen-film mammography screening (SFM) to full-field ...

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Gamma-glutamyltransferase activity in exosomes as a potential marker for prostate cancer

Exosomes or extracellular vesicles have the potential as a diagnostic marker for various diseases including cancer. In order to identify novel exosomal markers for prostate cancer (PC), we performed proteomic ...

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The long non-coding RNA HOTAIR enhances pancreatic cancer resistance to TNF-related apoptosis inducing ligand [Gene Regulation]

Pancreatic cancer is a malignant neoplasm with a high mortality rate. Therapeutic agents that activate TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis have shown promising efficacy, but many pancreatic cancers are resistant to TRAIL therapy. Epigenetic regulation plays important roles in tumor pathogenesis and resistance, and a recent study indicated that the long non-coding RNA HOX transcript antisense RNA (HOTAIR) is overexpressed in pancreatic cancer. However, the role of HOTAIR in pancreatic cancer resistance to anticancer agents is unknown. The present study determined the role of HOTAIR in pancreatic cancer TRAIL resistance and investigated the underlying molecular mechanisms. We observed that TRAIL-resistant pancreatic cancer cells had increased levels of HOTAIR expression, while TRAIL-sensitive pancreatic cancer cells had lower HOTAIR levels. Overexpressing HOTAIR in TRAIL-sensitive cells attenuated TRAIL-induced apoptosis, and shRNA-mediated HOTAIR knockdown in TRAIL-resistance PANC-1 cells sensitized them to TRAIL-induced apoptosis. These results support a causative effect of HOTAIR on TRAIL sensitivity. Mechanistically, we found that increased HOTAIR expression inhibited the expression of the TRAIL receptor death receptor 5 (DR5), whereas HOTAIR knockdown increased DR5 expression. We further demonstrated that HOTAIR regulates DR5 expression via the epigenetic regulator enhancer of zeste homolog 2 (EZH2) and that EZH2 controls histone H3 lysine 27 tri-methylation on the DR5 gene. Taken together, these results demonstrate that high HOTAIR levels increase the resistance of pancreatic cancer cells to TRAIL-induced apoptosis via epigenetic regulation of DR5 expression. Our study therefore supports the notion that targeting HOTAIR function may represent a strategy to overcome TRAIL resistance in pancreatic cancer.

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Insights into Catalysis of Lysine-Tryptophan Bond in Bacterial Peptides by a SPASM-Domain Radical SAM Peptide Cyclase [Microbiology]

Radical SAM enzymes are emerging as a major superfamily of biological catalysts involved in the biosynthesis of the broad family of bioactive peptides called ribosomally synthesized and post-translationally-modified peptides (RiPPs). These enzymes have been shown to catalyze unconventional reactions such as methyl transfer to electrophilic carbon atoms, sulfur to Cα-atom thioether bonds or carbon-carbon bond formation. Recently, a novel radical SAM enzyme catalyzing the formation of a lysine-tryptophan bond has been identified in Streptococcus thermophilus and a reaction mechanism has been proposed. By combining site-directed mutagenesis, biochemical assays and spectroscopic analyses, we show here that this enzyme, belonging to the emerging family of SPASM-domain radical SAM enzymes, likely contains three [4Fe-4S] clusters. Notably, our data support that the seven conserved cysteine residues, present within the SPASM-domain, are critical for enzyme activity. In addition, we uncovered the minimum substrate requirements and demonstrate that KW-cyclic peptides are more widespread than anticipated, notably in pathogenic bacteria. Finally, we show a strict specificity of the enzyme for lysine and tryptophan residues and the dependence of an eight-amino acids leader peptide, for activity. Altogether, our study suggests novel mechanistic links among SPASM-domain radical SAM enzymes and supports the involvement of non-cysteinly ligands in the coordination of auxiliary clusters.

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Structure of the Human Aminopeptidase XPNPEP3 and Comparison of its in-vitro Activity with Icp55 Orthologs: Insights into Diverse Cellular Processes [Enzymology]

The human aminopeptidase XPNPEP3 is associated with cystic-kidney disease and TNF-TNFR2 cellular signaling. Its yeast and plant homolog Icp55 processes several imported mitochondrial matrix proteins leading to their stabilization. However, the molecular basis for the diverse roles of these enzymes in the cell is unknown. Here, we report the crystal structure of human XPNPEP3 with bound apstatin product at 1.65 Å resolution and compare its in-vitro substrate specificity with those of fungal Icp55 enzymes. In contrast to the suggestions by earlier in-vivo studies of mitochondrial processing, we found that these enzymes are genuine Xaa-Pro aminopeptidases, which hydrolyze peptides with proline at the second position (P1'). The mitochondrial processing activity involving cleavage of peptides lacking P1' proline was also detected in the purified enzymes. A wide proline pocket as well as molecular complementarity and capping at the S1 substrate site of XPNPEP3 provide the necessary structural features for processing the mitochondrial substrates. However, this activity was found to be significantly lower as compared to Xaa-Pro aminopeptidase activity. Due to similar activity profiles of Icp55 and XPNPEP3 we propose that XPNPEP3 plays the same mitochondrial role in humans as Icp55 does in yeast. Both Xaa-Pro aminopeptidase and mitochondrial processing activities of XPNPEP3 have implications towards mitochondrial fitness and cystic-kidney disease. Furthermore, the presence of both these activities in Icp55 elucidates the unexplained processing of the mitochondrial cysteine desulfurase Nfs1 in yeast. The enzymatic and structural analyses reported here provide a valuable molecular framework for understanding the diverse cellular roles of XPNPEP3.

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Population-based assessment of racial/ethnic differences in utilization of radical cystectomy for patients diagnosed with bladder cancer

Abstract

Purpose

Radical cystectomy is a surgical treatment for recurrent non-muscle-invasive and muscle-invasive bladder cancer; however, many patients may not receive this treatment.

Methods

A total of 27,578 patients diagnosed with clinical stage I–IV bladder cancer from 1 January 2007 to 31 December 2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) registry database. We used multivariable regression analyses to identify factors predicting the use of radical cystectomy and pelvic lymph node dissection. Cox proportional hazards models were used to analyze survival outcomes.

Results

A total of 1,693 (6.1%) patients with bladder cancer underwent radical cystectomy. Most patients (92.4%) who underwent radical cystectomy also underwent pelvic lymph node dissection. When compared with white patients, non-Hispanic blacks were less likely to undergo a radical cystectomy [odds ratio (OR) 0.79, 95% confidence interval (CI) 0.64–0.96, p = 0.019]. Moreover, recent year of surgery 2013 versus 2007 (OR 2.32, 95% CI 1.90–2.83, p < 0.001), greater percentage of college education ≥36.3 versus <21.3% (OR 1.23, 95% CI 1.04–1.44, p = 0.013), Midwest versus West (OR 1.64, 95% CI 1.39–1.94, p < 0.001), and more advanced clinical stage III versus I (OR 29.1, 95% CI 23.9–35.3, p < 0.001) were associated with increased use of radical cystectomy. Overall survival was improved for patients who underwent radical cystectomy compared with those who did not undergo a radical cystectomy (hazard ratio 0.88, 95% CI 0.80–0.97, p = 0.008).

Conclusion

There is significant underutilization of radical cystectomy in patients across all age groups diagnosed with bladder cancer, especially among older, non-Hispanic black patients.



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Parental smoking, maternal alcohol, coffee and tea consumption and the risk of childhood brain tumours: the ESTELLE and ESCALE studies (SFCE, France)

Abstract

Purpose

To investigate whether parental smoking around the time of pregnancy or maternal consumption of beverages (alcohol, coffee, or tea) during pregnancy were associated with the risk of CBT.

Methods

We pooled data from two French national population-based case–control studies with similar designs conducted in 2003–2004 and 2010–2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender, were interviewed through telephone, which included questions about prenatal parental smoking and maternal consumption of alcohol, coffee and tea. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex and study of origin.

Results

No association was seen between CBT and the mother smoking or drinking alcohol, coffee, or tea during the index pregnancy. The OR between CBT and paternal smoking in the year before birth (as reported by the mother) was 1.25 (95% CI 1.03, 1.52) with an OR of 1.09 (0.99, 1.19) for every 10 cigarettes per day (CPD) smoked. The association between paternal smoking and CBT appeared to be stronger in children diagnosed before the age of five years (OR 1.52, 95% CI 1.14, 2.02) and for astrocytoma (OR 1.86, 95% CI 1.26, 2.74).

Conclusion

We found some evidence of a weak association between paternal smoking in the year before the child's birth and CBT, especially astrocytomas. These findings need to be replicated in other samples, using similar classifications of tumour subtypes.



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Melicope ptelefolia leaf extracts exhibit antioxidant activity and exert anti-proliferative effect with apoptosis induction on four different cancer cell lines

Melicope ptelefolia is a well-known herb in a number of Asian countries. It is often used as vegetable salad and traditional medicine to address various ailments. However, not many stu...

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Castanea sativa Mill. bark extract exhibits chemopreventive properties triggering extrinsic apoptotic pathway in Jurkat cells

Chemoprevention represents the possibility to prevent, stop or reverse the cancerogenetic process. In this context the interest towards natural extracts and botanical drugs has constantly grown due to their ph...

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The C-terminus of ribosomal protein uS4 contributes to small ribosomal subunit biogenesis and the fidelity of translation

Publication date: Available online 5 May 2017
Source:Biochimie
Author(s): Divya Kamath, Benjamin B. Allgeyer, Steven T. Gregory, Margaret C. Bielski, David M. Roelofsz, Sharon L. Sabapathypillai, Nikhil Vaid, Michael O'Connor
Ribosomal protein uS4 is an essential ribosomal component involved in multiple functions, including mRNA decoding. Structural analyses indicate that during decoding, the interface between the C-terminus of uS4 and protein uS5 is disrupted and in agreement with this, C-terminal uS4 truncation mutants are readily isolated on the basis of their increased miscoding phenotypes. The same mutants can also display defects in small subunit assembly and 16S rRNA processing and some are temperature sensitive for growth. Starting with one such temperature sensitive Escherichia coli uS4 mutant, we have isolated temperature insensitive derivatives carrying additional, intragenic mutations that restore the C-terminus and ameliorate the ribosomal defects. At least one of these suppressors has no detectable ribosome biogenesis phenotype, yet still miscodes, suggesting that the C-terminal requirements for ribosome assembly are less rigid than for mRNA decoding. In contrast to the uS4 C-terminal mutants that increase miscoding, two Salmonella enterica uS4 mutants with altered C-termini have been reported as being error-restrictive. Here, reconstruction experiments demonstrate that contrary to the previous reports, these mutants have a distinct error-prone, increased misreading phenotype, consistent with the behavior of the equivalent E. coli mutants and their likely structural effects on uS4-uS5 interactions.



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Characterization of the lipid envelope of exosome encapsulated HEV particles protected from the immune response

Publication date: Available online 5 May 2017
Source:Biochimie
Author(s): Sabine Chapuy-Regaud, Martine Dubois, Célia Plisson-Chastang, Tiffany Bonnefois, Sébastien Lhomme, Justine Bertrand-Michel, Bruno You, Steve Simoneau, Pierre-Emmanuel Gleizes, Benoît Flan, Florence Abravanel, Jacques Izopet
The hepatitis E virus (HEV) is the most common cause of acute hepatitis worldwide. Although HEV is a small, naked RNA virus, HEV particles become associated with lipids in the blood of infected patients and in the supernatant of culture systems. The egress of these particles from cells implies the exocytosis pathway but the question of the role of the resulting HEV RNA containing exosomes and the nature of the lipids they contain has not been fully addressed.We determined the lipid proportions of exosomes from uninfected and HEV-infected cells and their role in HEV spreading. We cultured a suitable HEV strain on HepG2/C3A cells and analyzed the population of exosomes containing HEV RNA using lipidomics methods and electron microscopy. We also quantified HEV infectivity using an infectivity endpoint method based on HEV RNA quantification to calculate the tissues culture infectious dose 50.Exosomes produced by HEV-infected HepG2/C3A cells contained encapsidated HEV RNA. These HEV RNA-containing exosomes were infectious but ten times less than stools. HEV from stools, but not exosome-associated HEV from culture supernatant, was neutralized by anti-HEV antibodies in a dose-dependent manner. HEV infection did not influence the morphology or lipid proportions of the bulk of exosomes. These exosomes contained significantly more cholesterol, phosphatidylserine, sphingomyelin and ceramides than the parent cells, but less phosphoinositides and polyunsaturated fatty acids.Exosomes play a major role in HEV egress but HEV infection does not modify the characteristics of the bulk of exosomes produced by infected cells. PS and cholesterol enriched in these vesicles could then be critical for HEV entry. HEV particles in exosomes are protected from the immune response which could lead to the wide circulation of HEV in its host.

Graphical abstract

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Specific roles of phosphatidylglycerols in hosts and microbes

Publication date: Available online 5 May 2017
Source:Biochimie
Author(s): Isabelle Dugail, Brandon D. Kayser, Marie Lhomme
Phosphatidylglycerols (PGs) are specific phospholipids bearing negatively charged polar headgroups. Although recognized for long as a major lipid component of membranes in bacteria, it is considered a minor lipid in higher eukaryotes, due to its low abundance in biological fluids or tissues. However, new sensitive lipidomic approaches now provide tools for accurate quantification of PGs in biological samples, and this is likely to uncover new roles for these phospholipids in the near future. This paper reviews our present knowledge in PG function, from studies in microbes and eukaryotic cells, and gathers in one place a diverse range of information spread across many fields. The physical properties of PGs, their biological distribution and molecular functions make them potential actors in host-microbe interaction.



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Individual and community level factors with a significant role in determining child height-for-age Z score in East Gojjam Zone, Amhara Regional State, Ethiopia: a multilevel analysis

In Ethiopia, child undernutrition remains to be a major public health challenge and a contributing factor for child mortality and morbidity. To reduce the problem, it is apparent to identify determinants of ch...

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Erratum to: Critical Congenital Heart Disease Newborn Screening Implementation: Lessons Learned



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A 12 month weight loss programme would be cost effective for NHS, study finds

GPs should refer overweight or obese adults to weight loss programmes for 12 months rather than the standard three months, researchers have recommended.1A study published in the Lancet reported that...
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