The increased use of nephron-sparing surgery to treat localized renal cell carcinoma (RCC) lends weight to the question of the value of microscopically positive surgical margins (PSM) in cases with a tumor bed macroscopically free of residual tumor. The aim of this article is to highlight the data available on risk factors for PSM, their clinical relevance, and possible therapeutic consequences. For this purpose, publications on the incidence and relevance of PSM after partial nephrectomy from the last 15 years were examined and evaluated. We summarize that PSM are generally rare, regardless of the surgical procedure, and are seen more often in connection with an imperative indication for nephron-sparing surgery as well as a central tumor location. Most studies describe that PSM lead to a moderate increase in the rate of local relapses, but no study has thus far been able to demonstrate an association with shorter tumor-specific overall survival. Intraoperative frozen section analysis had no positive influence on the risk of definite PSM in most trials. Therefore, we conclude that PSM should definitely be avoided. However, in cases with a macroscopically tumor-free intraoperative resection bed, they should lead to close surveillance of the affected kidney and not to immediate (re)intervention. In recent years, organ-sparing surgery for renal tumors in terms of partial nephrectomy or tumor enucleation has replaced radical nephrectomy as the standard procedure for treating locally confined renal cell carcinoma (RCC)–8. This However, no prospective and/or randomized study has yet been performed to investigate the prognostic significance of histopathologically positive but intraoperative macroscopically tumor-free surgical margins in predicting the risk of local relapse, metachronous metastases, and tumor-specific survival; only one nonsystematic review has been published thus far. MoreoveAccording to various studies, the incidence of PSM at final pathology is between 0 and 7% for open surgery–37, 1 toet al.[P = 0.01). Multivariate analysis also revealed a nearly five times higher risk of PSM after classic partial nephrectomy (P = 0.04). Minervini et al.[Data from smaller studies suggest that enucleation along the plane of the tumor pseudocapsule may be superior to classic partial nephrectomy with regard to the incidence of PSM. Verze et al. retrospei et al. comparedet al.[P = 0.02).Patients with an imperative indication for nephron-sparing surgery  have a higher incidence of larger and more unfavorably located tumors than the total patient population. This explains why an imperative indication could be identified as a risk factor for PSM in nearly all studies, at least by univariate analysis. PSM rates of 9 to 28% are described here, 53–55. et al. also ideet al.[et al.[According to a study by Kwon et al. in 770 p[et al. reportedet al.[et al.[et al.[It is still controversial whether tumor size has an impact on the PSM rate. While various research groups were unable to demonstrate a correlation, 43, othet al., for exaet al.. On the [et al. the PSM [et al. have alset al.[P < 0.001).It cannot yet be conclusively clarified whether tumor location within the kidney can influence the PSM rate, since none of the published studies included a reproducible nephrometry scoring system. However, available data suggest that PSM is observed more frequently after resection of centrally located tumors, 56. Benet al. proposed quick-staining cytology as an alternative to FSA in a recent publication and showed a good level of agreement with final histologic examination [Intraoperative frozen section analysis (FSA) to ensure tumor-free surgical margins is performed frequently and may reduce the rate of PSM, at least in some patient subgroups in laparoscopic surgery  grades 1 to 2 and 2 tumors). However<0.0001).et al.[et al.[et al.[It has not yet been conclusively clarified whether PSM increase the risk of local relapses after partial nephrectomy, even though the majority of studies suggest that this is probably the case, 56, 66.et al. found 26[et al. showed tet al.[P = 0.11) or tumor-specific overall survival (P = 0.4). Using multivariate analysis, an imperative indication for partial renal resection  and a central tumor location  proved to be independent risk factors for tumor relapse, but not PSM at final pathology[Bensalah et al. evaluateathology.et al.[P = 0.97). Multivariate analysis revealed that, unlike tumor size, PSM was not a risk factor for local relapse  or metachronous metastases .In another large study published by Yossepowitch et al., 77 out et al.[A study by Marszalek et al. with a met al.[P = 0.58). Multivariate analysis also failed to identify PSM status as an independent predictor of cancer-specific survival . Thus, microscopic PSM does not appear to significantly influence tumor-specific survival[et al. reported a HR of 3.45 (95% CI: 1.79 to 6.67) for cancer-specific survival in patients with PSM; however, one limitation of that study was the small number of PSM cases (n = 14) compared to total cohort size (n = 1801)[In a large study recently published by Ani et al., 71 of 6survival, 57, 67. = 1801).PSM should definitely be avoided even if a certain safety margin is no longer required in nephron-sparing surgery for renal tumors, 35. How


We investigated the effect of extra virgin (EV) olive oil and genetically modified (GM) soybean on DNA, cytogenicity and some antioxidant enzymes in rodents. Forty adult male albino rats were used in this study and divided into four groups. The control group of rodents was fed basal ration only. The second group was given basal ration mixed with EV olive oil (30%). The third group was fed basal ration mixed with GM (15%), and the fourth group survived on a combination of EV olive oil, GM and the basal ration for 65 consecutive days. On day 65, blood samples were collected from each rat for antioxidant enzyme analysis. In the group fed on basal ration mixed with GM soyabean (15%), there was a significant increase in serum level of lipid peroxidation, while glutathione transferase decreased significantly. Interestingly, GM soyabean increased not only the percentage of micronucleated polychromatic erythrocytes (MPCE), but also the ratio of polychromatic erythrocytes to normochromatic erythrocytes (PEC/NEC); however, the amount of DNA and NCE were significantly decreased. Importantly, the combination of EV olive oil and GM soyabean significantly altered the tested parameters towards normal levels. This may suggest an important role for EV olive oil on rodents’ organs and warrants further investigation in humans. Plant food represents a major source of nutrients for humans. As well as performing a protective role against chronic diseases such as coronary heart disease, diabetes mellitus and cancer ; plants Extra virgin (EV) olive oil is a vegetable oil obtained from olive trees (oleaeuropaea); a traditional tree crop of the Mediterranean Basin. It has many applications including cooking, cosmetics, pharmaceutical preparations and soaps. Olive oil is considered a healthy product because of its constituents, which include oleic acid, palmitic acid and other fatty acids; in addition to traces of squalence and sterols. There is considerable data demonstrating that the consumption of olive oil is beneficial to cardiovascular health; specifically it has a favorable effect on cholesterol regulation and LDL cholesterol oxidation. It has also been shown to have anti-inflammatory, antithrombotic, antihypertensive and vasodilatory effects in both animals and humans .Soyabean is considered to be one of the most important crops worldwide. It is generally considered to be a protein concentrate as this represents 42% of its make up .et al. [et al. [Ram et al.  found th [et al.  reported [et al.  reported [et al. ,9.The primary aim of this study was to elucidate any potential hepato-protective role that may be performed by natural products such as GM soyabean and whole EV olive oil. To accomplish this we examined their anti-oxidative effects, both individually and in combination, by investigating their effects on damage to DNA in rats. Interestingly, we found a possible protective role when animals are fed with a mixture of EV olive oil and GM soya bean and we believe this outcome represents an important opportunity to examine the potential benefits of these valuable natural products further.Forty adult white albino rats (Sprague Dawley strain) with an average weight of (150 to 180 g), were used in this study. They were obtained from the laboratory animal house of the ophthalmic research institute, Giza, Egypt. The rats were acclimatised to laboratory condition before the experiment began. They were fed according to the experimental design detailed later in the manuscript and supply was given ad-libitum. All experiments were conducted according to the University’s ethical protocols.Soyabean: Soyabean grind was purchased from a local market in Cairo, Egypt. It was freshly prepared and mixed with basal ration for rats, at a concentration of 15% .Extra virgin olive oil: was purchased from a local market in Cairo, Egypt. It was freshly prepared and mixed with basal ration for rats, at concentration of 30% . The cheForty adult rats were divided into four groups of ten. The experiment was conducted over 65 consecutive days. The feeding structure for each group is detailed in Blood samples were obtained from each animal group from their orbital plexuses and received into a clean, dry tube. Samples were left to clot at room temperature for 2 h, stored overnight in a refrigerator at 4 °C and centrifuged at 3000 revolutions per minute (rpm) for 15 min. Serum samples were then drawn in clean, dry capped bottles and kept in deep freeze at 4 °C for antioxidant enzyme studies. .et al. [et al. [Lipid peroxide was obtained using thiobarbitutric acid reaction outlined by Ohkawa et al.  and puri [et al. .et al. [et al. [The isolation of DNA from spleen of rats was performed according to the following protocol: first, the tissue was homogenized in isotonic saline buffered with sodium citrate (pH 7.0); protein was then removed by treatment with a chloroform/amyl alcohol mixture and the DNA precipitated with ethanol according to protocols established by Schwander et al. . Estimat [et al. .et al. [The micronucleus test was performed to detect chromosomal damage associated with treatment. Micronuclei were identified as dark blue staining bodies in the cytoplasm of the polychromatic erythrocytes (PCEs) according to the protocol mentioned by Salamon et al. . The polet al. ,18.Parametric data were interpreted using the analysis of variance (ANOVA) test and comparative of means were performed using the Duncan Multiple Range test  using SPThis study was carried out to investigate the effects of EV olive oil and GM soybean on DNA cytogenicity, as well as looking into its antioxidant role. To address these questions male albino rats were fed one concentration of each plant alone, or combined, for 65 days. We examined the antioxidant enzymes analyses and investigated in order to determine the DNA damage in the spleens and its cytogenicity, in rats.Diet effects on antioxidant enzymes: Feeding on ration mixed with GM soyabean at concentration 15% caused significant increase in serum level of lipid peroxidation, while the level of glutathione dehydrogenase was significantly reduced .Ration mixed with EV olive oil and GM soyabean significantly altered the serum level of antioxidant enzymes. This change was in the direction of the normal value when compared with the group fed on soyabean only .Diet effects on DNA: Maintaining rats on EV olive oil at concentration 30% for 65 days revealed a significant increase in the amount of DNA (ng/g of spleen) when compared with the control group. The amount of DNA (ng/g of spleen) significantly decreased when feeding rats GM soyabean (15%), while it increased significantly in rats fed EV olive oil (30%) and GM soyabean (15%) .Diet effects on cytogenicity: Feeding rats GM soyabean only caused a significant increase in micronucleated polychromatic erythrocytes (MPCEs) and the ratio of polychromatic to normochromatic erythrocytes (PCE/NCE). However, maintaining rats on ration mixed with EV olive oil and GM soyabean, instigated significant decrease of MPCEs and the ratio of PCE/NCE, though normochromatic erythrocytes (NCE) increased significantly when compared to the group fed soyabean only .EV olive oil is known to have a wide variety of benefits on many different body systems. This study was carried out to examine the effects of EV olive and G.M. soybean oil on DNA, as well as serum antioxidant enzymes.In our study, rats were fed EV olive oil, GM soya bean, or a combination of the two, at concentrations (30%) or (15%). The study was conducted over 65 consecutive days.We report a significant decrease in the level of lipid peroxidation and a significant increase in the level of glutathione dehydrogenase, when comparing the EV olive oil and GM soyabean combined group with GM soyabean fed animals only. These results may be attributed to the presence of antioxidants in EV olive oil, which has shown a number of positive effects on liver regeneration ,22,23.In addition, EV olive oil contains antioxidants and flavonoids that usually improve nutritional status and also has anti-inflammatory effects which may help in liver renewal ,25,26.Our data illustrates that the group of rats fed a mixed ration with EV olive oil for 65 successive days, showed a significant increase in the amount of DNA ng/g of spleen, when compared with the group maintained on soyabean alone.On the other hand, tests on the rats fed GM soyabean alone revealed a significant decrease in the amount of DNA ng/g of spleen; while the group that was fed a mixed ration of EV olive oil and GM soyabean showed a significant increase in the amount of DNA ng/g of spleen; with these changes in parameters appearing to fall into the normal ranges.et al. [et al. [et al. [et al. [The mechanism for the decrease in the amount of DNA was discussed by Zhou et al.  who repo [et al. , Amel et [et al.  and Vani [et al.  showed tet al. [et al. [et al. [et al. [Our results are in agreement with Salvini et al. , Jacomcl [et al.  and Quil [et al.  who repo [et al.  who statet al. [et al. [et al. [et al. [Fabiani et al.  suggeste [et al.  reported [et al.  and Fabi [et al.  describeet al. [The mechanism for the increase in DNA was explained by Lopez et al.  who illuet al. [et al. [et al. [Jeffery , Jee-Youet al. , Aiad [3et al. , Khataib [et al.  and Tudi [et al.  showed tet al. [Sekene et al.  concludeet al. [Rats fed a mixed ration with GM soybean showed a significant increase in MPCEs and in the ratio of PCE/NCE; while a significant decrease in NCE was observed. Feeding EV olive oil in combination with GM soyabean to rats, instigated a significant decrease in MPCEs and in the ratio of PCE/NCE and this helped to normalise their values. Suzuki et al.  describeet al. [Hanan et al.  reportedet al. [2+ induced mitochondrial swelling, mitochondrial membrane depolarization and intra-mitochondrial Ca2+ release on mitochondrial permeability transition (MPT). Moreover Sivikova et al. [The mechanism of reducing MPCEs and the ratio of PCE/NCE were explained by Tang et al.  who conca et al.  describeWe can conclude that adding EV olive oil to the diet of rats appears effective in inhibiting oxidative damage and may act as a protective agent against chronic diseases such as liver fibrosis, hyperlipidemia and diabetes. In addition, EV olive oil may also have a protective function against carcinogenic processes. Further clinical studies are therefore required to determine whether the observations observed in our study translate to human conditions and illnesses.


We critically re-examine Fredrickson et al.’s renewed claims concerning the differential relationship between hedonic and eudaimonic forms of well-being and gene expression, namely that people who experience a preponderance of eudaimonic well-being have gene expression profiles that are associated with more favorable health outcomes. By means of an extensive reanalysis of their data, we identify several discrepancies between what these authors claimed and what their data support; we further show that their different analysis models produce mutually contradictory results. We then show how Fredrickson et al.’s most recent article on this topic not only fails to adequately address our previously published concerns about their earlier related work, but also introduces significant further problems, including inconsistency in their hypotheses. Additionally, we demonstrate that regardless of which statistical model is used to analyze their data, Fredrickson et al.’s method can be highly sensitive to the inclusion (or exclusion) of data from a single subject. We reiterate our previous conclusions, namely that there is no evidence that Fredrickson et al. have established a reliable empirical distinction between their two delineated forms of well-being, nor that eudaimonic well-being provides any overall health benefits over hedonic well-being. Fredrickson et al.  claimed Recently, Fredrickson et al.  publisheWe previously noted  a numberWe ran essentially the same analyses as before  to test t test to non-independent data, namely the collected coefficients from multiple separate regressions of the expression of individual genes on measures of well-being. However, Fredrickson et al.  in identifying eudaimonic well-being as the primary source of associations between overall well-being and CTRA gene expression and provide no support for any independent favorable contribution from hedonic well-being. The consistency and robustness of these findings across 3 independent study samples also refutes claims that the initial discovery study findings were somehow spurious or unreplicable.  antiviral genes. This implies that the symmetric  association of the expression of pro-inflammatory genes with hedonic well-being, identified by Fredrickson et al. in their initial analyses of their discovery sample , should 2 metric) gene expression values” (p. 5) in their discovery and confirmation studies. In other words, this figure represents the results of applying their original regression method from [Fredrickson et al.  used thehod from  to both hod from  and theihod from , and, atFirst, as we have previously demonstrated , 4, Fredy-axis of that figure shows that it was not  shown in their Table 3 [used two different versions of the GSE45330 dataset in their article [Second, Fredrickson et al.’s original analysis  was greaWe note that Fredrickson et al. have recently issued a correction  to theirchange sign, and the remainder to undergo a substantial change in magnitude, whether Fredrickson et al.’s original RR53 regression method or their new mixed effect linear model was used. Specifically, in the case of the RR53 method, the fold difference value for hedonic well-being changes from +3.6% to −8.8% when this participant is excluded, while the value for eudaimonic well-being changes from −7.3% to +5.3%. In the case of the mixed effect linear model, the b-coefficients change from 0.536 to −0.120 (hedonic) and from 0.135 to 0.065 (eudaimonic). Click here for additional data file.


Feedback and closed-loop circuits exist in just about every part of the nervous system. It is curious, therefore, that for decades neuroscientists have been probing the nervous system in an open-loop manner to understand it. Instead of the linear, reductionistic “stimulate → record response” approach, a more modern approach is taking hold: closed-loop neuroscience. It respects the inherent “loopiness” of neural circuits, and the fact that the nervous system is embodied, and embedded in an environment. Through active sensing, behaving animals can influence their environment in ways that alter subsequent sensory inputs. Therefore, loops abound not only in the nervous system itself, but through its dynamic interactions with the world. By interposing our own technology in some of these loops, we can achieve unprecedented control over the system being studied and explore the functional consequences. This Research Topic, “Closing the Loop Around Neural Systems,” presents a diverse set of recent methodological, scientific and theoretical advances from neuroscientists and neuroengineers who are pioneering closed-loop neuroscience.As shown here, cutting-edge researchers are taking advantage of real-time or “on-line” processing of large streams of neural data. This has become feasible thanks to advances in computer processing power, in electronics such as microprocessors and field-programmable gate arrays (FPGAs), and in specialized and open-source software. These advances have enabled a wide variety of new neuroscience approaches to understanding, modulating, and interfacing with the nervous system—approaches in which the variables being monitored can influence the experiment in progress, just as active sensing can influence an animal's next input.Our call for submissions to this Frontiers in Neural Circuits Research Topic yielded an overwhelming response, indicating that closing the loop around neural systems is an exciting and rapidly expanding field. Perhaps this is because of the diversity of ways in which “closed-loops” can be interpreted and implemented. This Research Topic presents seven Methods articles, 16 Original Research articles, and seven Reviews, Mini-Reviews, and Perspectives, for a total of 30 accepted papers published in Frontiers in Neural Circuits between April 2012 and October 2013. A map showing the locations of all the contributorsin vitro and in vivo are described.Several articles describe or review new technologies that increase the options for closed-loop neuroscience. Two papers by Bareket-Keren and Hanein  and Robiin vitro. Bonifazi et al. (in vitro preparation and its response to focal ischemia. The goal is to develop the closed-loop prostheses of the future. Tessadori et al. (in vitro on an MEA with small tunnels for neurites to grow through. Pimashkin et al. (A number of articles present advances using acute or cultured networks i et al.  present i et al.  present i et al.  reconstrn et al.  used an in situ brainstem preparation of a mouse model for Rett syndrome. To help map the brain's feedback loops, Beier et al. (Others studied the nervous systems of intact or semi-intact animals with closed-loop approaches. Nishimura et al.  restoredr et al.  demonstrr et al.  provide r et al.  present r et al.  review hThe “Model-in-the-loop” paradigm is a powerful approach to understanding complex neural network dynamics. Brookings et al.  interfacTheoretical advances are described in several modeling and simulation papers. Witt et al.  modeled On the clinical side, Afshar et al.  describeThe diversity of methods, experiments, tools, and analyses in this Research Topic suggests that many more areas of neuroscience research would benefit from adopting a closed-loop perspective.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


By contrast, no significant benefit emerged for CBT when compared to active control conditions either at end-of-therapy  or at follow-up . The meta-analysis, however, contains errors and omissions that when rectified, cast doubt on the reliability of the reported significant effects comparing CBT to Treatment as Usual (TAU) at end-of treatment and at follow-up.In their meta-analysis, Mehl et al.  examine d = 0.27 to d = 0.14. Mehl et al. did not, however, report the 95% Confidence Intervals and whether the revised effect size is significant (rather they report the standard error: SE = 0.12)—the required analysis reveals that the revised effect size of 0.14 becomes non-significant (95%CI −0.07 to 0.35).First, for the end-of-trial analysis, Mehl et al. demonstrate the presence of significant publication bias. Their funnel plot is asymmetric and a trim-and-fill analysis points to four possible missing unpublished studies . They note that when effect sizes for the four “missing” studies are included, the original effect size almost halves from d = 0.94) alone is considered an outlier, but not Foster (d = 0.90) or Waller et al. (d = 0.89). The removal of a single outlier here is somewhat opaque and atheoretical.Second, Mehl et al. also highlight the moderate level of heterogeneity in their end-of-trial analysis and attribute this to one outlying study by Kråkvik et al. . After rd = 0.94), which might also have been influenced by difficulties in maintaining the blinding procedure.” If we turn to the Kråkvik et al paper itself, those authors clearly state that “All four professionals were trained in the use of assessment measures, but it was not possible to keep them blind to the treatment condition.” Mehl et al. also incorrectly classify Waller et al. (k = 9) elicit a non-significant effect size of d = 0.13 (95% CI −0.028 to 0.29) while non-blind trials  produce an effect size five-times larger with d = 0.65 (95% CI 0.21 to 1.09). Additionally, it is notable that amongst the nine blind trials, heterogeneity is virtually non-existent I2 = 4.8. In sum, the minority of non-blind trials underpins the inflation of effect sizes and their reported heterogeneity.Third, Mehl et al. give only a fleeting mention to the most well-documented, “genuine” and significant source of heterogeneity in CBTp trials—whether outcomes are measured blind or not  in favor of controls. If we add this new value to replace the apparently erroneous effect size reported by Mehl et al. a random effects model now shows the overall effect size reduces to 0.16 (−0.03 to 0.34) and becomes non-significant.Turning to the follow-up analysis, where Mehl et al. claim an overall significant effect of CBT on delusions with n et al.  which isn et al.  delusionTo summarize, examination of Mehl et al.'s end-of-trial data comparing CBT and TAU shows that if the overall effect size is adjusted for potential publication bias, then it becomes non-significant. Further analysis of the same data also shows that the significant heterogeneity reported by Mehl et al. is likely to reflect the inclusion of 4 non-blind trials, which elicit effects sizes five-times larger than in blinded trials. Analysis of nine blind trials revealed no heterogeneity and no CBT efficacy. Turning to the follow-up data, adjusting the effect size for Turkington et al.  means thThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, Maria Semkovska, and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Structural health monitoring (SHM) has gained a significant number of attentions from the engineering communities in the past two decades, which integrates the knowledge of a variety of disciplines including structural engineering, material science, computer science, signal processing, and data management –3. A maiTherefore, in the light of these considerations, this special issue was launched in this journal, an SCI-indexed international journal. The papers in this special issue present the most recent advances, progress, and ideas in the field of the SHM and integrity maintenance and its application. It includes smart, bioinspired, nanometer, wireless, and remote sensing technology, sensor placement and optimization strategies, data compression, cleaning, mining and fusing technology, pattern recognition, feature extraction and damage detection and assessment, design, retrofit, maintenance, renewal and risk management of civil infrastructure, and application of SHM for heritage structures, historical monuments, and old bridges.Structural health monitoring of civil infrastructure using optical fiber sensing technology: a comprehensive review” by X. W. Ye et al. presents a summary of the basic principles of various optical fiber sensors, innovation in sensing and computational methodologies, development of novel optical fiber sensors, and the practical application status of the optical fiber sensing technology in civil infrastructure monitoring. The paper “Dynamic responses and vibration control of the transmission tower-line system: a state-of-the-art review” by B. Chen et al. reviews the dynamic responses and vibration control of the transmission tower line system as well as the disaster monitoring and mitigation of the system subjected to dynamic excitations. The paper “Recent research and applications of numerical simulation for dynamic response of long-span bridges subjected to multiple loads” by Z. Chen and B. Chen addresses the key issues involved in dynamic response analysis of long-span multiload bridges based on numerical simulation technologies and the engineering applications of newly developed numerical simulation technologies for safety assessment of long-span bridges. The paper “A review on strengthening steel beams using FRP under fatigue” by M. Kamruzzaman et al. summarizes the existing FRP reinforcing techniques for fatigue damaged structural steel elements.After two-round peer reviewing, totally 55 research articles are received and 28 out of them are finally accepted for publication in this special issue. Among them, four papers are review articles. The paper “Damage identification for large span structure based on multiscale inputs to artificial neural networks” by W. Lu et al. proposes a structural damage identification method by combining the measured results from strain sensors and accelerometers in the noisy environment based on the artificial neural network. The paper “Damage assessment of two-way bending RC slabs subjected to blast loadings” by H. Jia et al. investigates the blast response and damage assessment of a two-way bending RC slab subjected to blast loadings. The paper “Structural damage identification based on rough sets and artificial neural network” by C. Liu et al. conducts the research on potential applications of the rough sets theory and the artificial neural network method for structural damage detection. The paper “Damage detection on sudden stiffness reduction based on discrete wavelet transform” by B. Chen et al. presents the damage detection on sudden stiffness reduction of building structures based on the discrete wavelet transform. The paper “Damage detection of structures identified with deterministic-stochastic models using seismic data” by M.-C. Huang et al. addresses a deterministic-stochastic subspace method for damage identification which has been experimentally verified to detect the equivalent single-input-multiple-output system parameters of the discrete time state equation.The following papers address the research work on structural damage detection. The paper “Integrated system of structural health monitoring and intelligent management for a cable-stayed bridge” by B. Chen et al. describes the integrated system for structural monitoring and intelligent management of the cable-stayed Zhijiang Bridge, China. The paper “Full-scale measurements and system identification on Sutong Cable-stayed Bridge during typhoon Fung-Wong” by H. Wang et al. analyzes the wind data and the structural vibration responses obtained from the SHM system installed on the cable-stayed Sutong Bridge, China, during a typhoon. The paper “Study on typhoon characteristic based on bridge health monitoring system” by X. Wang et al. investigates the typhoon characteristics by use of the measured data from the bridge health monitoring system instrumented on the Jiubao Bridge, China. The paper “Numerical simulation of monitoring corrosion in reinforced concrete based on ultrasonic guided waves” by Z. Zheng et al. predicts the location of the pitting corrosion in reinforced concrete based on the ultrasonic guided waves. The paper “Study on dynamic response measurement of the submarine pipeline by full-term FBG sensors” by J. Zhou et al. measures the dynamic responses of the submarine pipeline by use of the FBG sensing technology. The paper “Case study on the maintenance of a construction monitoring using USN-based data acquisition” by S. Kim et al. develops a ubiquitous sensor network for monitoring and maintenance of the building structure. The paper “In-line ultrasonic monitoring for sediments stuck on inner wall of a polyvinyl chloride pipe” by H. Seo et al. verifies the applicability and effectiveness of the ultrasonic monitoring of sediments stuck on the inner wall of polyvinyl chloride pipes.Other papers focus on the research related to the development of integrated SHM systems and novel sensing technologies. The paper “Numerical simulation on slabs dislocation of Zipingpu concrete faced rockfill dam during the Wenchuan earthquake based on a generalized plasticity model” by B. Xu et al. investigates the slab dislocation phenomenon of the Zipingpu concrete faced rockfill dam during earthquake. The paper “An improved multidimensional MPA procedure for bidirectional earthquake excitations” by F. Wang et al. develops an improved multidimensional modal pushover analysis method for estimating the response demands of structures subjected to bidirectional earthquake excitations. The paper “A methodology for multihazards load combinations of earthquake and heavy trucks for bridges” by D. Sun et al. presents a modified model considering the advantages of Ferry Borges-Castanheta's model and Turkstra's rule in converting the random process into the random variables for earthquake analysis. The paper “Experimental study of the seismic performance of L-shaped columns with 500 MPa steel bars” by T. Wang et al. addresses the experimental results of six L-shaped RC columns with 500 MPa steel bars for seismic performance assessment.The subsequent papers present the investigations on the structural performance under seismic excitations. The paper “Effects of outlets on cracking risk and integral stability of super-high arch dams” by P. Lin et al. presents the outlet cracking in the Goupitan and Xiaowan arch dams by use of the nonlinear finite element method. The paper “Real-time safety risk assessment based on a real-time location system for hydropower construction sites” by H. Jiang et al. proposes a method for real-time safety risk assessment for the hydropower construction site. The paper “Ant colony optimization analysis on overall stability of high arch dam basis of field monitoring” by P. Lin et al. conducts a dam ant colony optimization analysis of the overall stability of the high arch dam on the complicated foundation. The paper “Displacement back analysis for a high slope of the Dagangshan hydroelectric power station based on BP neural network and particle swarm optimization” by Z. Liang et al. presents a displacement back analysis for the slope using an artificial neural network model and particle swarm optimization model. The paper “Uplifting behavior of shallow buried pipe in liquefiable soil by dynamic centrifuge test” by B. Huang et al. carries out the dynamic centrifuge model test to investigate the uplifting behavior of the shallow buried pipeline subjected to seismic vibration in the liquefied site.The remaining papers in this special issue introduce the research outcomes on monitoring of hydraulic and geotechnical structures. The paper “


The purpose of this review was to build upon a recent review by Weigelt et al. which examined visual search strategies and face identification between individuals with autism spectrum disorders (ASD) and typically developing peers. Seven databases, CINAHL Plus, EMBASE, ERIC, Medline, Proquest, PsychInfo and PubMed were used to locate published scientific studies matching our inclusion criteria. A total of 28 articles not included in Weigelt et al. met criteria for inclusion into this systematic review. Of these 28 studies, 16 were available and met criteria at the time of the previous review, but were mistakenly excluded; and twelve were recently published. Weigelt et al. found quantitative, but not qualitative, differences in face identification in individuals with ASD. In contrast, the current systematic review found both qualitative and quantitative differences in face identification between individuals with and without ASD. There is a large inconsistency in findings across the eye tracking and neurobiological studies reviewed. Recommendations for future research in face recognition in ASD were discussed. Individuals with autism spectrum disorders (ASD) experience difficulties communicating, which impacts on involvement in social situations . Informa, and what the nature (advantage or disadvantage) and magnitude of any difference might be (quantitative differences). Weigelt et al. [Weigelt et al.  recentlyt et al.  presentet et al. cited bott et al.  includedt et al.  review),t et al. , by inveSeven databases were used to locate published scientific studies matching with the inclusion criteria. These databases were CINAHL Plus, EMBASE, ERIC, Medline, Proquest, PsychInfo and PubMed. The main search terms were “face recognition”, “autism” and “eye tracking”. Using Boolean operators, the following search strategy was used: (“face recogni*” OR “fac* perception” OR “fac* processing” OR “face identi*”) AND  AND (autis* OR Asperger OR “autism spectrum disorder”)Prior to selection of the final published articles, a screening of the titles and abstracts was conducted. After reviewing full text articles, a manual search was conducted through a search of the reference list of the selected articles.Due to ongoing change of the Diagnostic of Statistical Manual of Mental Disorders criteria of ASD throughout the years, the search was limited from year 2000 to May 2013. The latest diagnosis criteria of ASD can be obtained from the Diagnostic of Statistical Manual of Mental Disorders (DSM-5) , all typThe current review included the different types of ASD specified in the DSM IV, which included individuals with Autistic disorder, Asperger’s syndrome and Pervasive developmental disorder not otherwise specified (PDD-NOS) . A furthAn inter-rater reliability score of 0.94 was achieved after evaluation by two reviewers, the first author and an occupational therapy honours student, based on an inclusion and exclusion criteria of a set 50 randomly selected articles. Any discrepancies were resolved with consensus discussion.S1 Table) [The methodological quality of each article was assessed using Kmet form (1 Table) . This sc1 Table) . Scores S2 Table) were citation, level of evidence, ASD population, comparison group, age group, type of stimuli, intervention , methods, outcomes and results.The extraction of data was based on Cochrane Handbook for Systematic Reviews Section 7.3.a . The heaA narrative review approach was applied. The synthesisation and analysis of data were based on themes of recognition accuracy, reaction times, number of fixations, fixation duration and secondary outcomes of brain activation studies fMRI activation, EEG and MEG measures.Electronic searches located a total of 880 articles. A review of titles and abstracts were conducted and 720 articles were excluded. Evaluation of 131 full text articles was conducted to determine suitability. Based on the exclusion criteria, 106 articles were omitted. Three articles were identified after a manual search of the reference lists resulting in a final inclusion of 28 articles .The majority of the studies included were case-control studies with an exception of one individual case study. A total of 1329 participants were included. Eight studies utilised eye tracker technology for the measurement of visual search strategies. Ten studies examined differences in patterns of brain activity; EEG was reported in five, fMRI measurements in four, and MEG in one study.rd edition-faces subtest. There is currently no evidence on the reliability and validity of the Benton Facial Recognition test, however the Neuropsychological assessment purportedly demonstrates adequate to high reliability and validity [rd edition is a reliable assessment, there may exist issues regarding validity. Four studies utilised the fine grained face perception method, in which face recognition is achieved through successful discrimination between two or more faces with some changes in features of the recognition stimulus [Sixteen employed simple face perception methodology, with stimuli necessitating discrimination between two or more faces. Seven studies used facial memory methods and assed participant’s ability to remember faces after at least a 30 seconds interval between familiarisation and recognition . Severalvalidity . Kent [1validity  states tstimulus .S2 Table). Limitations of the studies included small sample sizes and inadequate descriptions of sampling strategy. The majority of the studies controlled the baseline characteristics for individuals with ASD and the TD individuals. However, the intelligence quotient (IQ) was not controlled in ten studies, which may produce a bias in the obtained results [S2 Table) [The methodological quality of the studies ranged from poor to strong ( results –22. Poss2 Table) , 20–29.Numerous types of stimuli were used in the selected studies with varying levels of experimental manipulations that Weigelt et al  refer toTo determine the absence or presence of quantitative or qualitative differences in face recognition in ASD, the studies were categorised under qualitative if the methodology involved face markers in face recognition, such as face inversion effects, part-whole effect, face space and thatcher . StudiesA total of 25 studies reported recognition accuracy. Zurcher et al.  investigIn a fine grained face perception test (faces in the encoding and familiarisation phases had subtle differences), adults with ASD demonstrated greater difficulty (p = 0.003) in recognizing faces compared with the control group . This stSeven studies investigated facial memory recall accuracy and employed measures with or without a standardised assessment. Out of the 28 included studies, three studies used Wechsler memory scale scores for both immediate and delayed memory , 39, 40.‘certain’, ‘somewhat certain’ and ‘guessing’. It was expected that when an individual is ‘certain’ the face recognition accuracy improves. This is present among TD children as performed better when they were ‘certain’ (p<0.01). However, memory awareness accuracy was improved when children with ASD indicated ‘guessing’ (p<0.05) in comparison to TD children. This indicates a possible delay in their memory awareness. Recognition accuracy was similar between both groups when they were ‘somewhat certain’. When accuracy was compared with adults with ASD, recall awareness was better in comparison to children with ASD. Due to the younger population used in Chawarska and Volkmar [Benton Facial Recognition Test is a standardised assessment which measures simple face perception and this was used in two studies , 32. The Volkmar , recogniDeruelle et al.  studied As shown in Majority of the studies achieved statistical differences, which signify that TD individuals performed better in facial recognition tasks in comparison to individuals with ASD. Overall, the quantitative measurements in face recognition were reported in 16 studies. Three of these studies reported mixed results. With the exclusion of the mixed results studies, a total of 11 studies out of the 13 quantitative studies (85%) reported reduced face recognition accuracy among individuals with ASD. Qualitatively, a similar pattern was observed as six out of the eight qualitative studies (75%) reported poorer face recognition in individuals with ASD. Therefore, the studies reviewed reported both qualitative and quantitative differences were observed in face recognition individuals with ASD.Six studies included reports of reaction time. In a Benton Facial Recognition test, Tehrani-Doost et al.  recordedAs shown in Measurements of fixation duration were discussed in all seven eye tracking studies. Bradshaw et al.  found noChawarska & Shic  comparedOverall, fixation duration comparisons in Sterling et al.  revealedOutcomes of fixation duration in Falkmer et al.  comparedA study by Wilson et al.  found noDue to the differences in the classification of the areas of interests across the seven identified studies in fixation duration, studies which classified the individual features of the face, more specifically the ‘eyes’ and ‘mouth’, were retrieved for further comparisons. Five studies were reported the results of fixation durations in the ‘eyes’ and ‘mouth’. Majority of these studies  reported similar fixation durations towards the ‘eyes’ and ‘mouth’, as illustrated in Four eye tracking studies measured number of fixations. In a part-whole effect study, Falkmer et al.  divided Examination of number of fixations in primary regions of the face  revealed that both ASD and TD groups exhibit higher preference for fixating on the eyes . There wInterestingly, Sterling et al.  concludeTrepagnier et al.  demonstrIn summary, individuals with ASD demonstrated a decreased in the number of fixations towards the ‘eyes’ or the inner features of the face, i.e., eyes nose and mouth among the group with ASD. However, there is a large inconsistency in findings among the analysis of number of fixations towards the ‘mouth’. A summary of the results are presented in The areas of interest investigated in Pierce and Redcay  were theGrelotti et al.  concludefMRI activation was analysed differently in Zurcher et al.  as it waIn conclusion, specific differences in fMRI activation were inconclusive, as presented in Previous research has demonstrated that the N170 component is involved in face processing . Bentin In McPartland et al. , individIt has been previously suggested that the ERP, P1 is associated with early visual processing modulated by attention . Both McAdditional discussion of other ERPs like P2, N250 and face-N400 components can be found in Webb et al. . Dawson As demonstrated in Kylläinen et al.  studied Overall, while the studies using imaging techniques demonstrated some patterns in brain activity  were apparently intact in individuals with ASD. However, two specific quantitative differences in face identity perception are described; namely a face-specific reduction in accurate recall and eye-specific discrimination deficit for individuals with ASD. The conclusions of the synthesis of studies not discussed by Weigelt et al. [Weigelt et al.  concludet et al.  and publt et al. . The fint et al. . Howevert et al. , this requantitative and qualitative face recognition processes in ASD. Studies involving different “face markers”, i.e., face inversion effects, face space and Thatcher illusion were classified under qualitative studies [Quantitative studies included studies with (1) a working memory component, (2) simple visual perceptual discrimination between different faces, (3) perceptual discrimination of similar faces with subtle differences in face features, and (4) standardized face recognition assessments [qualitative and quantitative differences can be ambiguous, which could suggest a possible inherent methodological limitation of this systematic review to address face recognition processes. Ideally, an alternative framework should have been developed for this purpose but that would then have made the extension of the previous review impossible.This systematic review inherited the theoretical framework adopted by Weigelt et al. , who pro studies . Quantities with  a workinqualitative or quantitative stimuli.The comprehensive review by Weigelt et al.  chose toqualitative and qualitative face recognition conclusions in visual search strategies and brain activation processes cannot be derived. However, the conclusion from this systematic review was based on the comparisons of 734 participants . Due to this, definitive . Despite limitations, it can be stated that most studies were scored as having good to strong quality based on Kmet forms. Furthermore, casecontrol study design is indeed the most appropriate design to investigate differences between individuals with ASD and their TD controls.The main limitation in the majority of the studies reported was low sample size. However, this is a common occurrence across most research due to difficulties relating to recruitment. Sampling strategy could be determined in a minority of studies and ten studies revealed possible confounding factors due to insufficient control of IQ at baseline. Possible type II errors were identified in fourteen studies Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(PDF)Click here for additional data file.


Empiricpost-hoc tests ranged between 0.09 and 0.96, falling well-below the usual threshold of 0.80 for 9/10 comparisons). Moreover, we were asked to use Bonferroni-corrections due to multiple testing. This resulted in a very conservative test strategy . Therefore, we reported descriptive effect sizes that are better indicators of the hypothesized impact of symmetry issues than statistical significance in case of underpowered comparisons  whereas for male stimuli the pattern—albeit less pronounced—ran into the reversed direction . Magnitude and opposed directedness of symmetry effects  preliminarily corroborate differences across gender and stimulus orientation subsets. These results were not mentioned in Bernard et al.'s . Moreover, the same post-hoc tests as in Bernard et al. . However, both proposed contrasts yield a calculated mean difference of d = 0.29, p = 0.096 and d = 0.35, p = 0.024 further adding to the positive evidence against the SBIH. Taken together with our finding that newly constructed symmetry-matched stimuli also yielded positive evidence against the SBIH  using their original stimuli in a counterbalanced design. In summary, hitherto mixed findings are reported based on the original stimuli from Bernard et al. (We agree with Bernard et al.  that thed et al. , 2015b td et al.  that exaThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Primary malignant melanoma of the oral cavity is a rare neoplasm, especially on the tongue. We report a case of mucosal melanoma at the base of the tongue, an extremely rare location (only about 30 cases have been reported in literature). The extension study doesn´t revealed distant metastatic lesions. The patient was treated by subtotal glossectomy and bilateral functional neck dissection. Tongue is one of the most difficult structures to reconstruct, because of their central role in phonation, swallowing and airway protection. The defect was reconstructed with anterolateral thigh free flap. Surgical treatment was supplemented with adjuvant immunotherapy. The post-operative period was uneventful. At present, 24 months after surgery, patient is asymptomatic, there isn´t evidence of recurrence of melanoma and he hasn´t any difficulty in swallowing or phonation. Key words:Malignant mucosal melanoma, anterolateral thigh free flap, phonation, swallowing. Primary malignant melanoma in oral cavity is rare neoplasm. It represents approximately 1.7 % of all melanomas and 6.3% of head and neck melanoma (A 51-year-old man with a clinical history of esophageal hiatal hernia, gastroesophageal reflux, hepatitis A in childhood and appendectomy was referred to our department due to an asymptomatic pigmented lesion in the base of the tongue. On examination, a black, pigmented and diffuse mass measuring approximately 3 X 3 cm in size was found on the base of the tongue Fig. . It was et al (et al (According Gutman et al , the preet al  or Rapinl (et al  series, l (et al . The tonl (et al . Reconstl (et al . After gl (et al . This cal (et al . When thl (et al . Ante-rol (et al . Becausel (et al . Anotherl (et al . However


Plasma sheet pressure increases to balance magnetic flux density increases in the lobes. Here we examine plasma sheet pressure, density, and temperature during substorm growth phases using 9 years of Cluster data . We show that plasma sheet pressure and temperature are higher during growth phases with higher solar wind driving, whereas the density is approximately constant. We also show a weak correlation between plasma sheet temperature before onset and the minimum SuperMAG AL (SML) auroral index in the subsequent substorm. We discuss how energization of the plasma sheet before onset may result from thermodynamically adiabatic processes; how hotter plasma sheets may result in magnetotail instabilities, and how this relates to the onset and size of the subsequent substorm expansion phase.During substorm growth phases, magnetic reconnection at the magnetopause extracts ∼10 As such, increases in the lobe magnetic pressure during substorm growth phases result in changes in the plasma sheet density and temperature. i et al.  and Kistr et al.  found tha et al.  that shoal. Lui, . Thus, iBoakes et al.,http://nssdcftp.gsfc.nasa.gov/spacecraft_data/omni/).Using 9 years of Cluster data, we statistically examine how the plasma and magnetic field in the magnetotail vary with solar wind energy input during substorm growth phases. Using new advances in the identification of magnetotail regions [ER in the magnetotail during the Northern Hemisphere summer. During each orbit, the spacecraft passed through the northern lobes, plasma sheet, and southern lobes, with the orbits sweeping from dawn to dusk each year.Between 2001 and 2009, the Cluster spacecraft orbited the Earth in a near-polar orbit, with an apogee of ∼19 Reme et al.,Balogh et al.,X < −10 ER and |Y | < 5 ER.Using data from the Cluster Ion Spectrometer Composition Distribution Function sensor (CIS-CODIF) [Juusola et al. [Newell and Gjerloev,Gjerloev, t) were calculated between 2001 and 2010 and filtered using a 60 min low-pass filter to remove short period variations. The median positive and negative changes were then calculated. Intervals during which dSML/dt was less (more) than the median negative (positive) change were labeled as expansion (recovery) phase times. The main difference between our method and that of Juusola et al. [Juusola et al. [ε function [Perreault and Akasofu,Akasofu, Morley et al.,In order to identify growth phase intervals, we isolated those times that were not during substorm expansion or recovery phases using a technique similar to a et al.  but appla et al.  is that a et al.  only conV is the solar wind speed, B is the interplanetary magnetic field (IMF) strength, θ is the clock angle of the IMF with respect to the Earth's magnetic dipole moment, and ℓ0 is a scaling constant equal to 7 ER.For each Cluster data point, we calculate the mean solar wind power input over the preceding 15 min using the 1 min resolution OMNI data and the function XZ and  database [Boakes et al.,Dunlop et al.,β were determined for the different regions based on statistical relations between β and magnetotail currents . These criteria compared well with other methods of region determination [Boakes et al.,XZ plane and Figure XY GSM plane.Figure d Figure b XY GSM ER2 in the XY plane (quartiles of 552 and 2239 ER−2) and 1728 ER−2 in the XZ plane (quartiles of 728 and 2944 ER−2). Figures Boakes et al.,Cluster provides good coverage of the lobes and plasma sheet, with a median sample density of 1376 data points per + + O+) pressure and magnetic pressure, (c) ion temperature, and (d) ion density in the plasma sheet against the 15 min averaged ε function for growth phase intervals. The overlaid boxes indicate the distribution of data points in deciles of the complete solar wind data set (rather than the subset of solar wind data cotemporaneous with the Cluster data set). The boxes show the medians (blue line), upper and lower quartiles (thick boxes) and upper and lower deciles (thin boxes). Since the binned Cluster data are not always well described by a symmetric normal distribution, we have chosen this method of display to highlight the characteristics of the data points that would be lost if the data were expressed as a mean and standard deviation.Figure ρ) of the entire data sets were 0.35 and 0.21, respectively, although correlating the shown medians gave ρ of 0.94 and 0.96, respectively. This general trend in the data supports the canonical substorm model: increased driving leads to increased magnetopause reconnection and loading of open magnetic flux into the magnetotail lobes, leading to increased flaring and increased pressure in the magnetotail. In a recent study, Liu et al. [ε function; thus, they are effectively independent. Pressure variations during the substorm may be related to solar wind driving, while solar wind pressure defines the initial pressure within the system, resulting in a spread of observed pressures.The magnetic pressure in the lobes Figure a and totu et al.  showed tAndre and Cully,Figures ρ for the entire data set of 0.31 and 0.83 for the shown median values. The median temperature increases by a factor of 2.9 between the lowest and highest driving deciles. The interquartile range also increases, showing that a greater range of temperatures was observed during intervals of high solar wind driving. In contrast, there is little variation in the median or interquartile ranges of density between different levels of driving  for the fits to all the data were less than 0.18, indicating that the spread of the data is not dependent on the solar wind driving. For the medians, R2 is higher than 0.95, indicating that the general trends in the data are well described by the model. We note that the cross-sectional area for individual events is dependent on the solar wind ram pressure, which can vary by a factor of 2 between storm and nonstorm intervals [Kistler et al.,where We expand this model to calculated plasma sheet temperature under the assumption of pressure balance in the magnetotail,β is given bythus the temperature in the plasma sheet for a given value of β = 0.35 and for constant density  and the medians of the total pressure (dashed line). We note that βPS can vary with Ti,PS and that a full expansion of this equation will be dependent on the plasma equations of state used.The grey lines in Figure Figure min) during the expansion phase, which can be taken as an indication of the intensity of the substorm, increases with temperature of the plasma sheet just prior to onset. The difference between the median SMLmin between subsequent groups is statistically significant, assessed using the Mann-Whitney-Wilcoxon test, beyond the 95% level. The spread of data is large (with interquartile ranges of up to 137% of the median) and the Spearman's correlation coefficient is low (ρ = 0.43) but statistically significant beyond the 99% level. These results show a weak link between substorm expansion phase magnitude and the plasma sheet temperature observed by Cluster prior to onset.The minimum SML  but this is expected if one considers that the substorm expansion phases heats a preheated plasma sheet.Tsyganenko and Mukai [Morley et al. [nd Mukai  developey et al.  that is Shue et al.,Kropotkin and Lui,Miyashita et al.,P = nkT, pressure varies with density, temperature, or both. Thermodynamically isothermal changes in pressure would result in variations in density at constant temperature, whereas adiabatic changes in pressure would result in temperature changes. Statistical studies examining the thermodynamics of the plasma sheet have concluded that the plasma sheet is predominantly thermodynamically adiabatic [e.g., Baumjohann and Paschmann,Goertz and Baumjohann,Pontius and Wolf,Erickson, Birn et al.,Baumjohann et al.,Huang et al.,ε function, we find that the increase in temperature with these components is comparable.Given that the magnetosphere's shape is defined by pressure balance between the solar wind and magnetospheric plasmas [e.g., Burlaga and Ogilvie, Richardson and Smith, Borovsky et al. [A relationship between the solar wind velocity and temperature has previously been shown [e.g., y et al.  also shoNagai et al.,Kistler et al.,Case studies [Lui,Rae et al.,Walsh et al.,Angelopoulos et al.,Nishimura et al.,Sergeev et al.,Rae et al.,Cheng and Zaharia,Pritchett and Coroniti,Lui [Our results can be interpreted as showing that thermal energy can be added to the plasma sheet during the substorm growth phase without the need for reconnection or a rapid reconfiguration of the magnetosphere. While this additional energy may be small , it may be significant, particularly in controlling substorm onset. The physics controlling the onset of the magnetospheric substorm are still the subject of rich debate. Both plasma instabilities [e.g., iti,Lui  showed tMorley et al.,Milan et al.,Our results have shown that plasma sheet temperature increases with increased solar wind driving, and that higher plasma sheet temperatures are associated with larger substorms. This link may not be causal but simply a reflection of the correlation between lobe magnetic flux and plasma sheet temperature and the correlation between stored lobe magnetic energy and substorm size [e.g., Using 9 years of Cluster tail observations, we have shown that the growth phase plasma sheet temperature is higher during intervals of higher solar wind driving. This is thermodynamically reasonable: work done on the plasma sheet by the increasing magnetic pressure in the lobes increases the internal energy of the plasma sheet; in an thermodynamically adiabatic magnetotail this energy cannot be easily and quickly extracted from the plasma sheet so its temperature rises. We note that we cannot fully deconvole the links between plasma sheet temperature and the components of the solar wind drivers that may increase the plasma sheet temperature through other mechanisms. Higher temperatures during intervals of high driving may increase the likelihood of the plasma sheet becoming susceptible to a number of instabilities thus increasing the likelihood of substorm onset. While the energy increase of the plasma sheet may be small compared to the total energy budget of a substorm, the thermodynamic processes and energization of the plasma sheet prior to substorm onset may be key determining onset times and substorm intensity.


A suite of near-identical magnetite nanodot samples produced by electron-beam lithography have been used to test the thermomagnetic recording fidelity of particles in the 74–333 nm size range; the grain size range most commonly found in rocks. In addition to controlled grain size, the samples had identical particle spacings, meaning that intergrain magnetostatic interactions could be controlled. Their magnetic hysteresis parameters were indicative of particles thought not to be ideal magnetic recorders; however, the samples were found to be excellent thermomagnetic recorders of the magnetic field direction. They were also found to be relatively good recorders of the field intensity in a standard paleointensity experiment. The samples' intensities were all within ∼15% of the expected answer and the mean of the samples within 3% of the actual field. These nonideal magnetic systems have been shown to be reliable records of the geomagnetic field in terms of both direction and intensity even though their magnetic hysteresis characteristics indicate less than ideal magnetic grains.Nonideal magnetic systems accurately record field directionWeak-field remanences more stable than strong-field remanences Ozima and Ozima, Coe, Thellier and Thellier, Paterson et al., Dekkers and Böhnel, Muxworthy and Heslop, Extracting the directional information recorded by natural remanent magnetizations (NRM) of thermal origin has long been shown to be relatively reliable regardless of the magnetic domain state of the particles within a rock [Evans et al., Muxworthy et al., Heider and Bryndzia, King et al., Krása et al., Krása et al. [Krása et al., Muxworthy et al., One practical way to resolve this problem is to experimentally quantify the behavior of PSD TRM, however, the experimental investigation of PSD behavior has its own set of problems: The geometry and size of a magnetic crystal strongly controls its magnetic properties, as does its spatial relationship with respect to other magnetic particles [a et al.  reportedKrása et al. [Krása et al. [The nanofabrication technique used in this study to make the new samples has been described extensively by a et al. . The sama et al.  and are Muxworthy and Williams, Muxworthy et al., Muxworthy and Williams, Muxworthy and McClelland, Krása et al., Krása et al., Most of the samples are in the middle of the PSD range [The thermoremanence measurements reported in this paper were all conducted at the Kochi Core Center, Kochi University, Japan, using a combination of a Natsurhara-Giken TDS-1 paleomagnetic oven and a single-sample 2G magnetometer. For normalization purposes, a saturation isothermal magnetization (SIRM) was induced in a field of 1 T using a Magnetic Measurements MMPM10 pulse magnetizer.Before making the measurements the samples were vacuum-sealed in quartz-glass capsules. The samples were fixed to the inside of the capsules using Omega CC high-temperature cement. Before vacuum sealing, the samples had been stored in alcohol since last reduced.Krása et al. [The samples were induced with a SIRM using a field of 1 T, followed by a TRM in a field of 60 µT on cooling from 650°C. Due to the shape of the quartz capsules both the SIRM and TRM could only be induced in the plane of the nanodots unlike the experiments reported by a et al.  who measThe samples' in-plane TRMs were then stepwise thermally demagnetized . The meaCoe [Riisager and Riisager, Walton, Krása et al., After the initial TRM experiments, six of the magnetically stronger samples were selected for a synthetic paleointensity study: DK0011, DK0023, DK0024-2, DK0124right, DK0127, and DK0131. The samples were first induced with a TRM in a field of 100 µT (the “NRM”), and a paleointensity study conducted following the standard double-heating protocol of Coe , with pTKrása et al., Arai plots with corresponding NRM demagnetization plots are shown for all the samples in Leonhardt et al. [q). Five out of the six samples passed the selection criteria; sample DK0131 (k) [Paterson, The results were analyzed with the ThellierTool v. 4.22) software of t et al.  (Table2)2 software DK0131 f failed e DK0131 d, and itKrása et al. [Krása et al. [During thermal demagnetization of the samples' thermoremanences, all the samples were found to be reliable recorders of the inducing-field direction , i.e., sa et al.  who founa et al.  found thRS/MSM ratios  over the susceptibility of ARM (χARM) , and they are again less likely for the larger particles during TRM acquisition.As the calculation of TRM per unit mass relies on a number of assumptions, we also plot the susceptibility of TRM (χM (χARM) b. The ARa et al. . For theThese differences between the EBL, crushed and hydrothermally grown samples shown in Day et al., Carvallo et al., Krása et al., The samples displayed wide TRM unblocking spectra and hysteresis behavior that are more akin to MD behavior , howeverThere are a number of factors that question the universality of the laboratory paleointensity study in this paper. First, for example, there is uncertainty in the magnitude of the effect of aligning the TRM field direction with the initial NRM direction in the paleointensity experiment on the final intensity estimate, though it is likely it would improve the accuracy. In future studies, it would be worth repeating these experiments for a range of different angles, unfortunately, that was outside the scope of this study as there was evidence that the samples may have chemically altered during the first paleointensity experiment. Second, the cooling rate for these samples was the same in both the NRM acquisition and TRM acquisition. Future laboratory experiments could investigate this, but it is difficult to generate geologically comparable long cooling times in the laboratory. Certainly, the viscous decay of TRM in such samples should be investigated in the future.Krása et al. [Ten samples produced by electron-beam lithography with near-identical grains in the pseudo-single domain size range have been induced with thermoremanences, and their thermomagnetic properties examined including their ability to record reliable paleointensity information. They were found to be reliable recorders of both the intensity and direction of the geomagnetic field. On comparison with a et al.  it is se


Helical polymers are found throughout biology and account for a substantial fractionof the protein in a cell. These filaments are very attractive for three-dimensionalreconstruction from electron micrographs due to the fact that projections of thesefilaments show many different views of identical subunits in identical environments.However, ambiguities exist in defining the symmetry of a helical filament when onehas limited resolution, and mistakes can be made. Until one reaches a near-atomiclevel of resolution, there are not necessarily reality-checks that can distinguishbetween correct and incorrect solutions. A recent paper in eLife almost certainly imposed an incorrect helical symmetry and this can be seen usingfilament images posted by Xu et al. A comparison between the atomic model proposedand the published three-dimensional reconstruction should have suggested that anincorrect solution was found.DOI:http://dx.doi.org/10.7554/eLife.04969.001 Helical polymers are ubiquitous in biology, and are found extensively in viruses , bacteriThe reconstruction of the MAVS filament presented in Wu et al. had a stated resolutionof 3.6 Å and had a helical symmetry of a rotation of −101.1° (thenegative rotation corresponding to a left-handed helix) and a rise of 5.1 Å persubunit. In contrast, the reconstruction of Xu et al. had a stated resolution of 9.6Å, a C3 point group rotational symmetry, with a rotation of −53.6° anda rise of 16.8 Å for every ring of three subunits. One of the differences betweenthe two reconstructions is that in Wu et al. not only are α-helices clearlyresolved, but bulky aromatic side-chains can be seen that are consistent with not onlythe sequence but a crystal structure of the subunit which can be fit quite well as arigid body into the reconstruction. In the Comment appended to their paper , Xu et aTheir first argument for a different helical symmetry is that a layer line at∼1/(17 Å) in their power spectrum has intensity on the meridian, while thecorresponding layer line in Wu et al. does not and is clearly arising from an n =−1 Bessel order. Is it possible that the sorting I have done for out-of-plane tilt is completely wrong,since it has involved the application of a helical symmetry, and the power spectrum inThe second argument advanced by Xu et al. in their Comment is that the symmetry used byWu et al. is unstable in the Iterative Helical Real Space Reconstruction (IHRSR)approach when applied to their filaments, and therefore their filaments must have adifferent symmetry. Since I developed the IHRSR method , I have The third and last argument advanced by Xu et al. in their Comment is that theirreconstruction has a hole in the center, while the model of Wu et al. that has beenbuilt into the 3.6 Å resolution reconstruction would have no such hole. Theycorrectly state that such a hole can be seen in their filaments independently of thesymmetry simply by cylindrically averaging their 3D density map. If one takes thecryo-EM density map deposited by Wu et al. (EMDB-5922) and filters it to 12 Åresolution a hole is seen in the center , arrow. I have thus shown that the three arguments for why their filaments are different fromthose of Wu et al., advanced by Xu et al. in their Comment, are not true. This does notestablish, however, that the filaments are the same. Establishing that would require ahigh resolution reconstruction from the filaments of Xu et al. which I fear would beimpossible. But we can look at their published reconstruction, which gets to the mostimportant point: given all of the potential problems and ambiguities in helicalreconstruction, how does one know that a structure is correct? The great success ofprotein x-ray crystallography lies in the fact that structures are being solved that allhave a known stereochemistry. One has prior knowledge about what an α-helix and aβ-sheet look like, as well as knowing the amino acid sequence that must be builtinto a model. At lower resolution by EM most of these reality-checks are simply absent,and one needs to generate methods, such as the tilt-pair validation used forsingle-particle cryo-EM  that canI show a comparison between their actual reconstruction , and theThis comparison between a map and a model can be made quantitatively, and In conclusion, the arguments of Xu et al. for a different symmetry in their filamentsthan that in Wu et al. collapse completely when one actually examines the publiclydeposited data.http://pdbe.org/empiar) from The micrographs in set04 within the EMPIAR-10014 deposition ( reviewprocess). Similarly, the author response typically shows only responsesto the major concerns raised by the reviewers.eLife posts the editorial decision letter and author response on a selection of thepublished articles . An edited version of theletter sent to the authors after peer review is shown, indicating the substantiveconcerns or comments; minor concerns are not usually shown. Reviewers have theopportunity to discuss the decision before the letter is sent , Wes Sundquist (Reviewingeditor), and three reviewers, of whom Niko Grigorieff and Carsten Sachse have agreed toreveal their identity. A third reviewer remains anonymous.Thank you for sending your work entitled “Ambiguities in HelicalReconstruction” for consideration at The Reviewing editor and the three reviewers discussed their comments before we reachedthis decision, and the Reviewing editor has assembled the following comments to help youprepare a revised submission.eLife . Thestudy by Xu et al. was published before a related study was published by Wu et al. inMolecular Cell . The situation merits follow-up because the two reported MAVS structures areentirely different. There is no dispute that the Wu et al. study contained high qualityEM data, that their reconstruction was technically correct, and that they successfullygenerated a near-atomic resolution structure of their MAVS filaments. The centralquestion is whether differences in sample preparation generated distinct MAVS filamentswith different physical structures, or whether the differences in the reportedstructures instead reflect methodological problems in the Xu et al study. Dr Jiang  has posted a Comment thataccompanies the original eLife manuscript in which he argues that thereported differences in the filament helical symmetries and structures reflect genuinephysical differences in the MAVS filaments generated by the two groups. Here, Egelmananalyzes the central claims of that Comment and also discusses the validity of theoriginal Xu et al. reconstruction.Dr Egelman analyzes the validity of a cryoEM helical reconstruction of the prion-likefilament formed by the CARD domain of the RIG-I adaptor molecule MAVS, as reported by Xuet al. in Egelman downloaded part of the original data deposited by Xu et al. in the EMPIAR database and performed image analyses to test the arguments put forth by Jiang that thefilaments used in the two studies were indeed different. He shows convincingly that thethree central pieces of evidence presented in the Jiang Comment are invalid. He makesseveral important points, including that Xu et al. did not appreciate that theirfilaments had significant out-of-plane tilt and that convergence stability in a symmetrysearch is not sufficient to establish the validity of that symmetry. Importantly, healso shows that the Xu et al. structure does not agree with its own PDB model beyond aresolution of ∼20 Å, suggesting that the computed EM density is not correct.These arguments convincingly rebut the points raised in Jiang's Comment, revealpotential inconsistencies in the processing procedure used by Xu et al., and raisesubstantial doubts about the validity of the Xu et al. reconstruction. These analysesare therefore an important contribution.The Egelman analysis could be strengthened even further by providing additional evidencethat Xu et al. must have imposed the wrong helical symmetry. The author could do this bycomputing a structure with the symmetry parameters from Wu et al. imposed on the EMPIARdata set from Xu et al. . Such a structure shouldcontain clearer densities and recognizable secondary structure features. […] The Egelman analysis could be strengthened even further by providingadditional evidence that Xu et al. must have imposed the wrong helical symmetry. Theauthor could do this by computing a structure with the symmetry parameters from Wu etal. imposed on the EMPIAR data set from Xu et al. . Such a structure should contain clearer densities and recognizablesecondary structure features.I have been able to improve the resolution that I initially obtained with their imagesby excluding those with a defocus greater than 3.0μ. This reduced the data setfrom ∼64k segments to ∼15k segments, but the reconstruction is clearlyimproved. I have expanded


The ribution , 4.et al. conducted a screen using a colon cancer cell line to identify small molecules in a National Cancer Institute (NCI) chemical library that could induce TRAIL on tumor cells and thereby activate TRAIL receptors via an autocrine or paracrine mechanism [http://oncoceutics.com/).To overcome the lack of activity of exogenous TRAIL ligands, Allen echanism . This scechanism . TIC10/Oechanism . With adet al. [et al. synthesized the reported structure to study its mechanism of action, it had no activity [et al. using NMR and X-ray crystallography [The isomeric structure of TIC10/ONC201 is critical to its activity , 7. The et al. , and theactivity . Subsequactivity . Interesactivity . The disDespite the structural mis-assignment of TIC10/ONC201, the preclinical studies support the therapeutic potential of TIC10/ONC201. Elucidation of the structure of TIC10/ONC201 will facilitate its preclinical and clinical development. Indeed, the inactive isomers begin to provide structure/function insight. As this research moves forward, however, the challenge will be to address the hurdles that have hindered development of TRAIL receptor agonists. Predictive biomarkers that identify sensitive and/or resistant cells will need to be developed so that studies can be targeted to cohorts of patients most likely to benefit from TIC10/ONC201 . In addi


Streptococcus, Enterococcus and Lactococcus contain large amounts of the sugar rhamnose, which is incorporated in cell wall-anchored polysaccharides (CWP) that possibly function as homologues of well-studied wall teichoic acids (WTA). The presence and chemical structure of many rhamnose-containing cell wall polysaccharides (RhaCWP) has sometimes been known for decades. In contrast to WTA, insight into the biosynthesis and functional role of RhaCWP has been lacking. Recent studies in human streptococcal and enterococcal pathogens have highlighted critical roles for these complex polysaccharides in bacterial cell wall architecture and pathogenesis. In this review, we provide an overview of the RhaCWP with regards to their biosynthesis, genetics and biological function in species most relevant to human health. We also briefly discuss how increased knowledge in this field can provide interesting leads for new therapeutic compounds and improve biotechnological applications.The composition of the Gram-positive cell wall is typically described as containing peptidoglycan, proteins and essential secondary cell wall structures called teichoic acids, which comprise approximately half of the cell wall mass. The cell walls of many species within the genera  This review summarizes new insights into the genetics and function of rhamnose-containing cell wall polysaccharides expressed by lactic acid bacteria, which includes medically important pathogens, and discusses perspectives on possible future therapeutic and biotechnological applications. N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) polysaccharide strands that are cross-linked by short peptides to form a three-dimensional network. Individual species tailor important physical properties of their peptidoglycan such as elasticity and porosity through the composition of the peptide bridge, the amount of crosslinking and chemical modifications of the composing glycan residues  that surrounds the cell membrane , such as capsular polysaccharides and wall teichoic acids (WTA), are anchored to peptidoglycan GlcNAc or MurNAc, covering the bacterium with a layer of glycans that is directly exposed to the environment  and Streptococcus agalactiae (Group B Streptococcus), have emphasized the critical role of these molecules in cell wall biogenesis and pathogenesis . L-rhamnose is commonly found in bacteria but is not used or produced by humans  and Streptococcus lactis (Lancefield Group N). Today, more than 150 different species are known within these three genera, which remain classified within the order Lactobacillales . We focus here on the species relevant to food production and human health and with experimental evidence for the presence of RhaCWP: Lancefield Groups A, B, C, E and G Streptococcus represented by S. pyogenes, S. agalactiae, Streptococcus equi subsp. zooepidemicus, Streptococcus mutans and S. dysgalactiae subsp. equisimilis, respectively, as well as E. faecalis and L. lactis.Although the direct correlation between Lancefield serotyping and species clearly no longer persists, bioinformatic analyses of genome sequences indicates that many of the species within these three genera express RhaCWP   versus a 2 side chain in the Group C Carbohydrate (GCC), respectively  and G carbohydrate (GGC), rhamnose is the major antigenic determinant acetylation and hydroxylation. Their biosynthesis requires the coordinated action of glycosyltransferases (enzymes that link monosaccharides), transporters and metabolic enzymes for the production of nucleotide-sugar precursors. Often, genes encoding proteins required for glycoconjugate biosynthesis are clustered on the chromosome. Their identification allows subsequent structure–function studies that help to understand the role of glycosylation in bacterial (infection) biology.et al. et al. et al. et al. et al. S. agalactiae, the availability of the GBC structure and genome sequence enabled a comprehensive and detailed in silico analysis that linked protein-encoding genes to the different glycosidic linkages in the GBC structure , Salmonella enterica (RmlC and RmlD) and Streptococcus suis (RmlB and RmlC), demonstrated that rhamnose biosynthesis enzymes require dimerization or even dimerization of dimers to catalyze the respective enzymatic reactions  elongation of the polysaccharide (building block) on the lipid carrier by sequential addition of activated sugar precursors, (3) translocation of lipid-linked precursors, either repeating units or the complete glycoconjugate, across the membrane by ABC transporters or ‘flippases’  and (4) by a dedicated polymerase. Since undecaprenylphosphate serves as a common scaffold to build structurally diverse glycoconjugates including capsules, peptidoglycan, lipopolysaccharides and protein-modifying glycans, the availability of ‘free’ undecaprenylphosphate is essential for bacterial survival  genes in E. coli and subsequent disruption of the ABC transporter-encoding genes (rgpCD), the bacteria were unable to produce rhamnan  as well as two integral membrane proteins (encoded by gbs1483 and gbs1490) that may act as accessory proteins . However, the presence of an additional glycosyltransferase compared to the GAC gene cluster in S. pyogenes suggests some fine structural variation. Likewise, the GBC has been reported to be expressed by different streptococcal species most notably Streptococcus porcinus, Streptococcus pseudoporcinus, Streptococcus troglodytidis and Streptococcus plurextorum. Correspondingly, the genomes of S. pseudoporcinus and S. porcinus contain a fully syntenous GBC biosynthetic gene cluster except for the lack of a gbs1485 orthologue (unpublished observations). Presumably, the expressed structures only lack one of the monosaccharide rhamnose side-branches present in the GBC repeating unit  and this species is non-groupable by Lancefield serotyping assays. Instead of gbs1481 and gbs1485, the S. thoraltensis locus harbors two additional glycosyltransferases absent in the otherwise syntenous locus of S. agalactiae . Absence of a gbs1481 orthologue is likely responsible for abrogated cross-reactivity in the Group B antigen serotyping tests due to the loss of the terminal rhamnose from the dominant trirhamnosyl epitope. This analysis therefore suggests that S. thoraltensis is capable of synthesizing a RhaCWP that is a structural variant of the GBC. Increased availability of genome sequences for streptococci and related species will help identify additional rmlD-linked gene clusters for RhaCWP biosynthesis that are consistent with either known Lancefield serotyping reactions (as exemplified here by S. castoreus) or from which variant or novel RhaCWP structures can be predicted.As mentioned above, the Lancefield typing scheme is unable to discriminate bacteria up to the species level. The availability of genome sequences, as well as knowledge regarding RhaCWP gene clusters, provides an opportunity to gain insight into the distribution and potential structure of RhaCWP among Gram-positive bacteria. For example, nit Fig.   of S. agalactiae to initiate functional studies on the GBC. The resulting GBC-negative S. agalactiae strain was devoid of cell wall rhamnose and phosphate and lost expression of the pellicle structure  by tunicamycin resulted in depletion of GAC from the cell wall, increased mutanolysin susceptibility and increased chain length as a result of cell separation defects (van Sorge et al. S. agalactiae gbcO mutant increases capsule production suggesting a coordinated regulation between the two glycoconjugates (Beaussart et al. Since their identification and structural characterization from the 1930s onwards, the biological roles of the Lancefield Group antigens or other RhaCWP have received little attention. It was long thought that Group-specific antigens were only of structural importance McCarty . Indeed,. et al.  targetedet al. et al. 2 side chain of the GCC serves as an attachment site for Group C1 bacteriophage in Group C Streptococcus (Krause 2 epitope, was isolated from Group C Streptococcus that survived exposure to Group C1 lytic phages (Krause S. pyogenes, the GAC-specific GlcNAc terminal moiety appears to be involved in both lytic and temperate phage adsorption although additional unidentified cell wall factors are also involved (Fischetti and Zabriskie S. mutans strains (Shibata, Yamashita and van der Ploeg L. lactis, selection of phage resistant strains from a random insertional mutagenesis library originally identified the presence and genetic locus of the RhaCWP (Dupont et al. et al. et al. et al. E. faecalis Epa through genetic manipulation greatly affect phage sensitivity despite similar adsorption levels (Teng et al. et al. L. lactis, knowledge regarding the molecular mechanisms of phage adsorption and infection may benefit the food industry.In addition to their significant role in cell wall architecture, it is appreciated that RhaCWP are important phage receptors for many species. This again highlights a parallel with WTA in other Gram-positive bacteria where WTA is critical to phage-mediated horizontal gene transfer (Baptista, Santos and Sao-Jose s Krause . Corresps Krause . Also foet al. et al. S. pyogenes and E. faecalis now highlight that subtle modifications to the RhaCWP structure, which do not impact bacteria growth, can significantly impact virulence (Xu et al. et al. et al. E. faecalis, disruption of epaB, epaE, epaM and epaN, which may completely eliminate Epa expression or only modify its structure, all caused significant attenuation in a mouse peritonitis model (Xu et al. et al. et al. L. lactis, loss of the pellicle results in 10-fold more efficient uptake by macrophage cell lines compared to wild-type bacteria (Chapot-Chartier et al. L. lactis and E. faecalis. For S. pyogenes, structure–function studies focused on the role of the GAC GlcNAc side chain, which was selectively removed through genetic mutation of the glycosyltransferase-encoding gene gacI (van Sorge et al. . The gacI mutant bacteria still expressed the rhamnan backbone but did not display apparent cell wall abnormalities. However, bacteria were increasingly susceptible to innate immune clearance by neutrophils and antimicrobial components (van Sorge et al. et al. et al. et al. et al. et al. et al. et al. et al. The localization of RhaCWP at the host–pathogen interface suggests that their biological function might be broader than a role in cell wall biogenesis. Similarly for WTA, evidence is accumulating for its role in virulence by increasing adherence and immune evasion (Carvalho S. pneumoniae capsule as a key virulence factor has been established since the 1928 landmark ‘Griffiths experiment’ and the capsular polysaccharides are major protective antigens utilized in current vaccine formulations (Geno et al. rmlABCD genes (Bentley et al. S. pneumoniae population and at least nine of the serotype antigens included in the current 23-valent vaccin are rhamnose-containing polysaccharides (Geno et al. Rhamnose is not just incorporated in RhaCWP, but is also present in capsular polysaccharides. We consider this structure distinct from RhaCWP given their localization in the cell wall; RhaCWP are interpolated within the peptidoglycan wall layer, whereas capsular polysaccharides are typically the outermost layers of the cell envelope. Nevertheless, it is worth noting that several clinically relevant Gram-positive bacteria synthesize rhamnose-containing capsules. The significance of the S. pneumoniae, S. agalactiae strains belonging to serotype VIII contain rhamnose within the polysaccharide repeating unit (Kogan et al. et al. et al. et al. In addition to et al. P. aeruginosa with some marginal activity against M. tuberculosis (Alphey et al. S. aureus, where inhibition of the UDP-GlcNAc:lipid phosphate transferase TarO is not detrimental to the bacterium, but render the bacterium avirulent (Sewell and Brown S. aureus (Campbell et al. Increased knowledge regarding the biosynthesis and function of RhaCWP could aid the development of new antimicrobial agents but may also have applications in metabolic engineering to optimize food production (Chapot-Chartier S. pyogenes and S. agalactiae. Indeed, different strategies are currently explored to develop protective vaccines against these streptococcal species (Dale et al. S. agalactiae (Johri et al. S. pyogenes (Dale et al. et al. S. pyogenes vaccine antigen. Conjugate vaccines of either isolated or synthetic GAC protect mice from subsequent infection after active and passive immunization (Sabharwal et al. et al. et al. et al. et al. in vitro and protected mice from lethal challenge with wild-type S. pyogenes through passive immunization (van Sorge et al. RhaCWP are also attractive vaccine candidates due to their conserved and constant expression in species of medical importance, such as et al. Finally, dissection of the RhaCWP biosynthesis pathway could benefit food production, most notably the dairy industry that uses lactic acid bacteria for food fermentations (Chapot-Chartier Despite their long history in streptococcal diagnostics, investigations on the biological roles and possible applications of RhaCWP have lagged behind. Genome sequencing has initiated genetic studies to elucidate structure–function relationships of RhaCWP, highlighting their critical importance in proper cell wall architecture and pathogenesis. Their indispensable nature identifies the RhaCWP biosynthesis pathway as an attractive therapeutic target for antimicrobial drug development. Spin offs will likely find applications in the area of metabolic engineering for food production and biomedical purposes.Supplementary DataClick here for additional data file.