Half of all cancer patients may receive radiotherapy as part of their treatment. With the wealth of diverse data generated every day in the clinic, the radiation oncology community possesses a unique advantage in harnessing these massive data with the predictive power of machine learning methods for the benefit of millions of cancer patients undergoing radiotherapy worldwide. In this Research Topic “Machine Learning with Radiation Oncology Big Data,” a wide range of clinical applications involving various machine learning algorithms have been described and demonstrated, with the hope of ushering in more widespread applications of artificial intelligence in medicine, particularly in cancer radiotherapy in order to achieve a truly individualized radiation oncology and an evidence-based learning healthcare system.Zhang et al.- Knowledge-based treatment planning: Tseng et al.- Knowledge-based response-adapted radiotherapy: Elhalawani et al., Jethanandani et al.- Radiomics image analysis: Kang et al.- Radiogenomics and outcome modeling: Jackson et al.,  Ali et al., Men et al.- Automated contouring and nodule detection: Sanders and Showalter.- Comparative effectiveness research: Feng et al.- Machine learning in radiation oncology overview: Gabryś et al.- Normal tissue complication probability modeling: Elhalawani et al. summarized the feedback of eight contestants who participated in a recent radiomics challenge in head and neck radiation oncology, and discussed some of the challenges in sharing and directing existing datasets toward clinical implementation of radiomics in radiation oncology.In this review paper, Tseng et al. discussed recent development in the knowledge-based response-adapted radiotherapy for personalized radiotherapy management. They addressed three specific questions that are necessary to realize it clinically: (1) what knowledge is needed, (2) how to estimate radiotherapy outcomes accurately, and (3) how to adapt optimally.Kang et al. presented an overview of machine learning algorithms in the application of radiogenomics to combine genomics signatures with radiotherapy. They summarized the important lessons learned for the proper integration of machine learning into radiogenomics analysis.Jackson et al. introduced a convolutional neural network approach for fully automated contouring of kidneys and automated radiation dose estimation in an unsealed source therapy, which provides comparable accuracy to humans while largely reducing the planning time.Jethanandani et al. explored the various applications of radiomics in magnetic resonance imaging of head and neck cancer, and identified the lack of standardization in study design as a major limitation to their clinical relevance.In a systematic review, Sanders and Showalter described their vision of combining big data with comparative effectiveness research methodologies within the framework of a rapid-learning healthcare system in order to accelerate discovery and realize a fully individualized radiation treatment.Feng et al. identified specific opportunities in a long chain of radiotherapy processes where machine learning could improve the quality and efficiency of patient care in radiation oncology, as well as the needs required to realize them at both the community and institutional levels.Ali et al. presented a robust non-invasive deep reinforcement learning method to predict the presence of lung nodules, a common precursor to lung cancer, based on 888 lung CT scans of the lung nodule analysis (LUNA) challenge.Zhang et al. proposed an ensemble approach to knowledge-based intensity modulated radiation therapy treatment planning, and demonstrated its advantages in terms of robustness against small training set sizes, mis-labeled cases, and dosimetric inferior plans.Gabryś et al. investigated whether machine learning with dosimetric, radiomic, and demographic features can allow for more precise xerostomia risk assessment. They identified the need for the development of personalized data-driven risk profiles for normal tissue complication probability (NTCP) modeling.Men et al. developed an end-to-end deep deconvolutional neural network for segmentation of nasopharyngeal tumor volumes to improve the consistency of contouring and streamline radiotherapy workflows, but cautioned that careful human review and a considerable amount of editing would still be required.The 11 papers included in this Research Topic produced some promising results and offered visionary perspectives regarding the role of machine learning with radiation oncology big data. The clinical applications demonstrated here are considered just the tip of the iceberg of the incoming full-spectrum applications of human intelligence and artificial intelligence in radiation oncology. While still in its infancy stage, we envisage that artificial intelligence together with human intelligence can provide something much better than either one could perform alone in the near future.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Dear Editor,We have read the article by Meillon et al.  with greChandra et al.  presenteThe majority of the evaluated surgeries were performed under peribulbar or retrobulbar anesthesia. Lid ecchymosis, as a hemorrhagic complication, was present in 1 out of 804 patients. The complications of local anesthesia in cataract surgery were meticulously investigated by Alhassan et al.  in the CFinally, we would like to congratulate the authors for their excellent study in this very important field.


The export of newly synthesized proteins from the endoplasmic reticulum is fundamental to the ongoing maintenance of cell and tissue structure and function. After co-translational translocation into the ER, proteins destined for downstream intracellular compartments or secretion from the cell are sorted and packaged into transport vesicles by the COPII coat protein complex. The fundamental discovery and characterization of the pathway has now been augmented by a greater understanding of the role of COPII in diverse aspects of cell function. We now have a deep understanding of how COPII contributes to the trafficking of diverse cargoes including extracellular matrix molecules, developmental signalling proteins, and key metabolic factors such as lipoproteins. Structural and functional studies have shown that the COPII coat is both highly flexible and subject to multiple modes of regulation. This has led to new discoveries defining roles of COPII in development, autophagy, and tissue organization. Many of these newly emerging features of the canonical COPII pathway are placed in a context of procollagen secretion because of the fundamental interest in how a coat complex that typically generates 80-nm transport vesicles can package a cargo reported to be over 300 nm. Here we review the current understanding of COPII and assess the current consensus on its role in packaging diverse cargo proteins. Compartmentalization of cells is a common feature of all eukaryotes. This necessitates a transport system to traffic proteins between these compartments. The first membrane trafficking step for most newly synthesized membrane and secretory proteins is from the endoplasmic reticulum (ER) to the Golgi. The transport of proteins out of the ER is enabled by the coat protein complex type II (COPII) vesicles. Since our lab wrote a review on this topic in this journal in 2008  is caused by mutations in Sec23B . Originally named as a gene product fused to the Trk receptor, TFG has since been defined as a key component of the ER exit site , involved in the export of lipoproteins from the ER, has recently been shown to be involved in ERES structure , as well as TANGO1 and KLHL12 , has been shown to occur in interphase [. The Golgi-localized protein kinase CK1δ (Lord et al. Drosophila, mechanisms have been described that operate to protect the core COPII machinery at times of cellular stress such as amino acid starvation (Zacharogianni et al. The balance between protein folding and ER export is an under-developed area of the COPII field. There is substantial evidence of an important and direct role for COPII in multiple aspects of ER quality control. Notably, an atypical role for COPII has been described in segregating misfolded proteins within the ER (Kakoi et al. As with most areas of classical molecular cell biology much remains to be discovered about the COPII system. How it is adapted in different tissue contexts, in different organisms, and at different stages of development (Ishikawa et al. Salmonella (Santos et al. Listeria (Gianfelice et al. E. coli, and Citrobacter (Thanabalasuriar et al. COPII has defined roles in viral replication including the turnip mosaic virus (Jiang et al. The role of core membrane trafficking pathways in neuronal function remains a relatively underdeveloped field. Dendritic development requires the COPII pathway (Ye et al. Considerable advances in cell biology have been made using small molecule inhibitors. There is some scope here for further development and some early work in this area has already identified potential inhibitors of COPII-dependent budding (Yonemura et al. Our core understanding is also likely to be significantly advanced by more specific and targeted genetic manipulation. The possibilities of functional genomics, genome editing, and further work in model organisms are almost endless. Coupled with the impact of new imaging modalities (Liu et al.


Dear Editor,in vitro tests in toxicology is that a compound is either tested as toxic or non-toxic in vitro and this prediction is then compared to the human in vivo situation for validation. The performance of such binary classification tests is assessed by established metrics, for example, sensitivity as the proportion of actual toxic compounds that were predicted as such; or sensitivity that measures the proportion of compounds that are non-toxic and were correctly predicted as non-toxic by the in vitro test. A frequent scenario concerning predictive in vivo. Recently, Albrecht et al. , informs how well toxic blood concentrations in vivo can be estimated by the in vitro test system. The advantage of these new performance measures is that they can be used to optimize test systems. For example, the authors showed that the use of an EC10 instead of EC50 for cytotoxicity analysis in hepatocytes leads to a higher TSI. Moreover, TEI was improved, when gene expression was included into the test battery, meaning that the lower alert concentration of both, cytotoxicity and gene expression resulted in a better TEI than using the alert concentration of each test individually. Therefore, the TSI and TEI concept allows to modify a test and learn whether the modified version performs better than the original one. Of course, conclusions drawn from a training set of compounds need to be validated in an independent compound set to avoid overfitting. However, measures of the performance of binary classifications become suboptimal, when concentration or dose-dependent analyses are performed and the tests aim at predicting doses that cause an increased risk of toxicity in vivo toxicity by in vitro tests , partical., 2017, 2016[6]al., 2017; Jansen al., 2017), cardioal., 2017; Chaudhaal., 2017), develoal., 2017; Krug etal., 2017) and neual., 2017; Meléndeal., 2017; Shinde al., 2017, 2016[16The author declares no conflict of interest.


In doing so, Brocklehurst et al. cite earlier studies to the same effect dating back to 2009 by Schachner et al. [Brocklehurst et al.  present et al. ,3. The lr et al. ,5.et al. neglected to cite my even earlier work, starting in 2001 [et al. hypothesis [et al.My concern is that Brocklehurst  in 2001 –8, whichpothesis , first pet al. analyses cite my studies, they too did not explicitly relate that I had previously examined the contrasts between bird and crocodilian ribcage morphologies and came to similar conclusions. Perhaps that failing to cite the precedent literature contributed to Brocklehurst et al.'s ignorance of who first considered and refuted the Ruben et al. hypothesis.They are not the first to fail to cite some of my innovative arguments on the subject of archosaur respiration. It is especially pertinent to this discussion that while the two Schachner et al. 2009 and 2011 papers in my 2012 discussion of the subject because I was not aware of them. Had I known of the studies I would have included them, the more to support the anatomical comparative hypothesis I originated.I regret that I did not cite the Schachner Hopefully, this note will cause those in the future working on this aspect of archosaur evolution to cite the precedent literature properly, whether or not they agree with it.


This special issue is dedicated to the simulation as well as experimental studies of biomechanical behavior of biomaterials, especially those that are used for bone implant applications. It is worth noting that orthopedic trauma (fractures) alone represented one-half of all the disease or injury-related hospitalizations in 2004–2005 . IndividIn the research article written by Mebarki et al. , a solutThe effect of varying levels of medial collateral ligament deficiency on elbow joint stability was studied by Rahman et al.  using suDuring the last decade, the use of bioresorbable metals in biomedical applications  has been an area of considerable interest, with numerous investigations working towards the development of biodegradable bone fixation hardware and stents. Amerinatanzi et al.  developeThe last article in the special issue, written by Nematollahi et al. , provideBioengineering for their valuable contributions.The guest editing team of this special issue would like to thank the authors as well as the staff of


People commonly reach for over-the-counter (OTC) pain medications to treat even the slightest physical discomfort, whether at work, at home, or on the go. Acetaminophen  tops the charts among popular painkillers, with estimates in the United States suggesting that nearly one in four adults consume a drug containing acetaminophen each week (Kaufman et al., An evolutionary mismatch occurs when there is a major divergence between modern contexts and ancestral environments (reviewed by Li et al., The experience of physical pain provides a clear example of a psychological adaptation. The unpleasantness of physical pain is highly adaptive and critical for survival. Pain draws our attention and serves to motivate responses to alleviate the discomfort. In ancestral conditions, this would have resulted in behavioral changes that functioned to reduce harm, minimize further damage, and prompt us to learn to avoid situations and actions that led to pain in the past. These benefits of physical pain are clearly witnessed among individuals unable to detect it, as those born with the rare condition of congenital insensitivity to pain often die in childhood due to the failure to notice injuries. Thus, there has been continuous selective pressure during the course of evolution to detect and reduce physical discomfort, and as a result most people possess a strong desire to avoid pain through behavioral changes that reduce exposure to harmful stimuli or events.Within modern environments, however, individuals suffering from pain can now bypass behavioral changes and simply treat their symptoms with OTC medication. In fact, acetaminophen has been recommended as the first line of treatment for acute lower back pain (reviewed by Koes et al., A distinct, yet somewhat similar, evolutionary mismatch comes from the fever reducing properties of acetaminophen and many other OTC pain medications. Research shows that acetaminophen and other OTC painkillers are effective and well-tolerated in treating febrile illness (McIntyre and Hull, More recent and thought-provoking lines of research show that acetaminophen can produce further mismatch with our evolved psychology by even diminishing our sensitivity to social experiences that are interpreted as painful or distressing (reviewed by Ratner et al., In a radical set of studies, DeWall et al.  found thFuture research should aim to examine the full range of psychoactive effects produced by acetaminophen and other OTC painkillers. Based on evidence supporting a general cortical dampening produced by acetaminophen (DeWall et al., To date, research examining the psychological effects of acetaminophen and other OTC painkillers is still in its infancy (Ratner et al., The author confirms being the sole contributor of this work and has 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.


Cancer is still a global challenge worldwide with a high impact not only on human health, causing morbidity and mortality, but also on economics. Although significant advances have been obtained in early diagnosis and in the development of new drugs, there is still a need of new molecules that contribute to span and improve the actual therapeutic strategies.Natural compounds from animal, microbial, vegetal, or fungi origin represent countless sources of new compounds that can be used as anticancer drugs if their activity, bioavailability, and toxicity are adequate. There are some general  and specIn this special issue original research manuscripts including both pure compounds and whole natural extracts have been included. Chiang et al.  have useThis special issue also contains data on the use of whole extracts and complex mixtures. Araki et al.  present Momordica cochinensis seeds [The last original manuscript of this special issue also studies a complex mixture of natural compounds. Le et al. studied the anticancer potential of a whole natural extract obtained from is seeds . They peReviews are also included in this special issue covering different topics with significant relevance regarding cancer research. Two of these reviews are focused on the pure compound resveratrol. Resveratrol is a stilbene with a long list of biological activities , includiGreen tea polyphenols have been also reviewed in this special issue. Miyata et al.  present Probiotics are also included in this special issue. Hendler et al.  update tA global perspective on the use of natural compounds in cancer treatment is taken by Herranz et al. in their review . In thisFinally, this special issue has met its original objective, contributing to increase the scientific evidence on the use of natural compounds in cancer research and treatment. However, there is a long way ahead, and new studies and evidence must be obtained in the future. Nature is a limitless source of new drugs, but these new drugs must always be supported by strong scientific evidence.


These sAltogether, deciding for and following a specific career path is a developmental process  Wolter et al.), emotional aspects to empathy as predictor for math achievement , and cognitive aspects relate to visuospatial skills that are often seen as key aptitude for STEM with a clear gender difference in favor of men. Abad et al. as well as Sanchis-Segura et al. look deeper into the issue of visuospatial skills raising the point that tests for the respective skills are often subject to gender framing, a background context, that affects their results. Such background contexts can be also found in Hsieh et al.'s work that focuses on ethnicity and immigrant status as predictors for motivational beliefs.Person inputs may affect self-assessments, motivation, behavior, and thus attainments and can be seen as a starting point for a career path into STEM. If, for example, a person finds his or her aptitude in STEM lacking and conceives her or his talents being outside of STEM, she/he is hardly likely to go into a STEM field. Person inputs are investigated with respect to motivational, emotional, cognitive, or socio-demographic aspects. In the studies presented in this Research Topic motivational aspects relate to goal orientations  Sachnis-Segura et al., who discuss how tests for visuospatial performance are constructed (favoring predominantly men), and by Hsieh et al. and Watson et al. who both discuss differences between ethnicities that may include different cultural values.Background contextual affordances relate to culture and cultural norms in which a person is embedded. They provide an indirect impact on all contributions of this Research Topic. The impact of this factor becomes most obvious in the contributions by Learning Experiences(3) Banchefsky et al.;Deiglmayr et al.;Höhne and Zander). In a long-term process, learning experiences are related to attainments, outcomes, and subsequent feedback and thus mostly need a longitudinal design for their investigation. In the Research Topic, several longitudinal studies are concerned with these variables, especially Dietrich and Lazarides and Hsieh et al. who investigate the development of motivational belief patterns, and Vinni-Laakso et al. as well as Watson et al. who focus on the long-term development of students' self-concept.Learning experiences play a major role in the model of Lent et al.  by shapiSelf-Efficacy and Self-Concept Expectations(4) Watson et al. looks closer into the gender-related decline of the self-concept in mathematics. Factors contributing to such processes and to the development of a student's self-concept for STEM in general are investigated by Heyder et al. who explore the impact of teacher expectations as well as by Höhne and Zander who analyze the impact of belongingness. The impact of the self-concept on further developments is investigated by Han who analyzes the relationship between self-concept and achievements, by Luttenberger et al. as well as by Sobieraj and Krämer who focus on the relationship between self-concept and motivation in STEM, and by Saß and Kampa who investigate the impact of self-concept profiles on course selection. Finally, Dietrich and Lazarides as well as Vinni-Laakso et al. analyze to which degree motivational belief patterns are associated with math-related career plans.Self-efficacy expectations, for example, are subject-specific academic self-concept or ability beliefs. Self-efficacy expectations are a crucial aspect of career paths into STEM and often vary by gender. Large scale studies such as PISA OECD,  confirm Expectations About Outcomes(5) Deiglmayr et al. as well as Höhne and Zander investigate in a sample of female students and the degree to which such beliefs are associated with uncertainty and feelings of not belonging to the domain of STEM even though these students major in a STEM field. Luttenberger et al. investigate the degree to which such beliefs predict motivation in STEM and Lazarides and Lauermann explore how beliefs may affect students' career plans. Hsieh et al. as well as Dicke et al. analyze how such beliefs develop over a long range in different STEM subjects and finally Bailey et al. investigate STEM and non-STEM undergraduates as well as academics discussing to which degree undergraduates' beliefs about talent in academia mirror those of academics.While self-efficacy expectations focus on the estimation of one's own ability, outcome expectations result from an assessment to which degree one's own skills are sufficient to achieve satisfactory outcomes in a field. In this sense, Kessels  discusseContextual Influences Proximal to Choice Behavior(6) Bailey et al. investigate contextual influences exerted by others and take up the hypothesis, that university graduates transfer their  ability beliefs to undergraduates. Such phenomena are in the scope of several contributions of this Research Topic focusing on the influence of teachers , parents , or the peer-group . Apart from these personal influences, STEM subjects are often generally attributed stereotypically as being male, an aspect that is taken up by Makarova et al. as well as by Watson et al., and consequently female students in STEM often choose contexts that are to a lower degree regarded as being typically male subjects, for example biology instead of physics contexts if they are able to choose (see Wheeler and Blanchard). Such stereotypical perspectives may be reinforced by representations in TV, which is investigated by Wille et al. Generally, such stereotypical as well as traditional gender role beliefs taken up from personal contexts predict lower educational attainment and less inclination for studying STEM subjects—an issue that is investigated by Dicke et al.Thereby, Interests and Task Values(7) Song et al. investigate the impact of interest and effort on persistence. However, as Schorr discusses, interest is often subject to pre-conditions including personal competency and outcome expectations. Similarly, Sobieraj and Krämer analyze to which degree self-perceptions are conjoined with interest-related characteristics such as intrinsic motivation. In this sense, Ertl and Hartmann as well as Watt et al. bridge the gap between interest and motivational profiles and respective choice goals and actions. Lazarides and Lauermann investigated this relation with respect to task values and career aspirations.Interests develop and deepen partly due to an individual's self-efficacy and outcome expectations—however, they are also shaped by contextual influences, for example, when interests are regarded as being inappropriate for a specific gender or when pursuing them seems to require too much effort  Ertl and Hartmann analyze to which degree students' interests fit to their career aspirations and they find a worse fit between interest and aspirations for STEM than for other subjects. Watt et al. identify different motivational profiles and discuss that especially disengaged students show lower STEM aspirations. Motivation and motivational belief-patterns and their impact on career plans are also discussed by Dietrich and Lazarides as well as by Lazarides and Lauermann, while Vinni-Laakso et al. analyze the impact of self-concept profiles on science course selection. Makarova et al., finally, expand the view on choice-goal section by discussing the impact of gender-science stereotypes on students' choice goals.Choice goals can be defined as students' career aspirations that either can go along with a student's interests or reveal deviations. Here, Choice Actions(9) Saß and Kampa aim at explaining science course selection by the impact of self-concept profiles. Sobieraj and Krämer apply a retrospective approach for explaining differences between STEM and non-STEM master students with respect to competence, motivational, and volitional variables.Specific choice actions are less predominant in the Research Topic, possibly because the transformation from a choice goal to a choice action is difficult to observe and to operationalize. Despite of such difficulties, Performance Domains and Attainment(10) Banchefsky et al.) and to interest . Regarding outcomes, Ghazy et al. analyze the role of empathy for math achievement and math scores and find different effects for male and for female students. Han also focuses on math performance scores and find a stereotype effect impeding female pupils. Similarly, Wille et al. investigate STEM stereotypes in a learning context and their differential effects on scores, stereotype endorsement, and belongingness. Sanchis-Segura et al. find similar effects for visuospatial tasks. The effect of framing tasks differently is investigated by Wheeler and Blanchard focusing on how biological contexts may facilitate female students' familiarizing with the context of force rather than traditional physics contexts. Hoferichter and Raufelder investigate the impact of parents' support and pressure on STEM performance and disclose differential effects for female and male students.Ideally, those who have embarked on a STEM career and show persistence should experience satisfying outcomes such as high attainments , feelings of belonging, joy, or life satisfaction. The two contributions which look closer into these concepts show that students' persistence in STEM is related to a feeling of belonging  to adult STEM professionals . In between, all stages of formal education are well-covered including primary school , lower secondary school , and upper secondary school  with a clear focus on university education . Some of these contributions focus on longitudinal developments, for example Abad et al. on the development of visuospatial skills, Dietrich and Lazarides as well as Hsieh et al. on the development of motivational belief patterns, Hoferichter and Raufelder on grades and parental influences, Vinni-Laakso et al. and Watson et al. on students' self-concept, and Dicke et al. on the development of STEM professionals.A specific aim of this Research Topic is to shed light on critical incidents or milestones on a STEM pathway over the life-span. Therefore, the topic covers evidence from kindergarten , with respect to specific subjects as for example in comparisons of mathematics and biology (Hoferichter and Raufelder); research can also refer to science in general  or to a range of different subjects in the field of STEM . Contributions that focus on one subject mostly investigate mathematics as key subject in STEM , followed by computer science  and physics (Wheeler and Blanchard). To uncover the special characteristics of STEM, some authors compare STEM subjects with NON-STEM . The remaining contributions focus on rather general aspects regarding STEM .Although the term STEM raises the impression of being a homogeneous academic domain, there are different definitions which vary in their broadness and some of them even include life sciences and social sciences into STEM (for a discussion, see Ertl et al., Luttenberger, Steinlechner et al. finally comment on the development on an individual's STEM pathway from interests to a career goal and choice actions and its respective facilitation by shedding light on the importance of early career-related learning experiences as well as on removing external barriers on the path into STEM.BE, SL, RL, MJ, and MP wrote this editorial.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.


In their correspondence, Hays et al. raise two main critiques of our recently published article entitled “Use of the KDQOL-36™ for assessment of health-related quality of life among dialysis patients in the United States.” First, Hays et al. expressed concerns regarding the comparison of mean scores on five Kidney Disease Quality of Life (KDQOL) subscales, given that the Physical Component Summary (PCS) and Mental Component Summary (MCS) are scored on a different numeric scale compared to the other three subscales. Second, Hays et al. note that the correlations reported in our manuscript between the general health perceptions item  and the 5 KDQOL subscales were inconsistent with findings derived from other KDQOL datasets. Here, we respond to these two critiques. We appreciate the detailed review and commentary on our manuscript  providedHays et al. raised an important question with regard to the correlation of the general health rating item and the 5 subscale scores as reported in our manuscript. Upon review, we have determined that indeed the correlations reported in our manuscript were based on analyses that included a coding error. This was an honest mistake that was not captured at the time of submission, and we thank Hays et al. for bringing this to our attention. Upon reanalysis, we find correlations that are broadly consistent with those reported by Hays et al., and our manuscript will be corrected to reflect these findings. Importantly, we have conducted a detailed review of the entire dataset and analysis underlying the remaining results presented in the manuscript and found no additional errors. Thus, we stand by all of the other results and conclusions as originally presented.Improving health-related quality of life, and the tools for its evaluation, remains a top priority for the entire end-stage kidney disease (ESKD) community. Like Hays et al., we believe that successful efforts in this regard will require the combined efforts of patients, providers, and researchers working in both industry and academia. We remain fully committed to participation in these collaborative endeavors.


Oxytocin in mutually-gazing humans and dogs: Rewarding or stress bonding?Nagasawa et al.  build onNagasawa et al.  proposedless on angry faces (Kis et al., eye region of angry faces while physiological arousal was lower (Somppi et al., We want to draw attention to findings that demonstrated that oxytocin may alter social attention by suppressing vigilance toward threatening social stimuli, which explains many of its observed prosocial effects. Moreover, altered social attention may be implicated in a role of oxytocin in social habituation processes, particularly in mammals, whereby an individual decreases their response to an unfamiliar, dominant, or emotional social stimulus after repeated exposure (Ebitz et al., aversive avoidance responses to newborns or potential partners (Insel and Young, Research from animals and human studies suggest a primal function of oxytocin in threat perception, with oxytocin reducing Oxytocin may facilitate attachment formation between humans and dogs through its function in threat-coping responses which increase trust (Tops et al., social reward often neglect the potential role of stress habituation and do not collect measures to support or refute these distinct theories. Taking the results of Nagasawa et al. (Studies which focus on identifying the role of oxytocin in a et al.  for examImportantly, both threat response and positive valence may direct gazing behavior, but the current study does not let us distinguish the two. Moreover, oxytocin responses triggered by low-level threat and by social reward and protection in other contexts may still be implicated in beneficial effects of living in good relationships with dogs impacting on human well-being, coping and health (Julius et al., As the first author, MT was involved in all steps of the process, and was the primary writer of the text. SH and FB-P contributed to the write-up.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.


Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system. I.The integrin receptor family plays a role in a variety of processes including the development of various tissues et al., et al., et al., The structure of integrins is well characterised and has been described in many reviews via many proteins. Firstly, talin, which interacts with the cytoplasmic tail of integrins, links them directly, or via vinculin, to the actin cytoskeleton. Secondly, focal adhesion kinase (FAK) is recruited to activated integrins and is a key signalling scaffold protein that activates downstream proteins such as paxillin and Src. Thirdly, integrin‐linked kinase (ILK) is another important signalling scaffold protein that phosphorylates downstream proteins. Conversely, ‘inside‐out’ signalling refers to the mechanism in which intracellular proteins bind integrins thereby inducing a conformational change that enhances the binding activity of integrins towards their ligands in the ECM, enabling intracellular signalling. Talin and kindlin, the main mediators of inside‐out signalling, are subject to various regulatory pathways that thereby affect integrin function et al., et al., in utero), leading to death by 4 weeks of age in the majority of cases  which in the CNS includes neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells in situ hybridisation and reverse transcription polymerase chain reaction (RT‐PCR) studies et al., In order to assess the subcellular localisation of integrin receptors, immunohistochemical approaches or expression of labelled integrins are required. Determining whether integrins are expressed in the axonal or somatodendritic compartment is useful for understanding their potential function. In this regard, numerous studies have examined integrin expression in cultured cells, with fewer studies documenting expression in tissue sections. There are many studies demonstrating integrins in axons during embryonic development, using both immunohistochemistry and staining of cultured embryonic neurons. This is not surprising; integrins are necessary for axon growth during development . Some studies however have succeeded in localising endogenous integrins specifically (see Table (3)et al., et al., et al., et al., et al., et al., et al., The neurons that have been shown to regenerate most readily are also those in which integrins are localised within axons. It is therefore interesting to link the subcellular localisation of integrins to the regenerative ability of the nervous system. As discussed above, DRGs express high levels of integrins in their axons and at least some RGC axons contain integrins (see Table (4)et al., et al., Discussion on the diverse function of integrins in the somatodendritic compartment is beyond the scope of this review but a recent review can be found in Park & Goda . FurtherIII.et al., et al., et al., et al., et al., et al., Certain integrins are up‐regulated after peripheral nerve injury (Kloss (1)et al., et al., in vitro studies have shown that laminin promotes adhesion, migration and regeneration of sensory axons and Schwann cells. The laminin‐interacting integrins are α1β1, α2β1, α3β1, α6β1 and α7β1 with each bearing different affinities for the different isoforms of laminin et al., et al., et al., via an Arg‐Gly‐Asp (RGD) domain, which is also found on other matrix molecules such as tenascin‐C and some laminins.Fibronectin is another important component of the ECM that stimulates the pro‐regenerative state of PNS neurons. Fibronectin is a large glycoprotein that consists of two subunits which form a dimer  receptor in inflammatory cells. α4β1 and α5β1 integrins are expressed at high levels in native DRG neurons and growth cones of regenerating neurons et al., et al., et al., et al., et al., et al., et al., et al., in vivo. It would therefore be interesting to explore whether activation or overexpression of the collagen‐associated integrins is beneficial for regeneration in the PNS.Collagen is another ECM molecule that is highly up‐regulated after peripheral nerve injury and is synthesised by Schwann cells and fibroblasts et al., et al., et al., et al., et al., et al., et al., Tenascin‐C is a ligand for integrins et al., et al., in vitro, while neurite outgrowth was largely absent in controls  could enhance axonal regeneration (discussed in Section VI.3c).We hypothesised that low or absent integrin expression in CNS axons  (reviewed in Kwok (1)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., in vitro et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., 2+, thereby inducing clathrin‐mediated endocytosis of integrins from the growth cones of Xenopus laevis spinal neurons  is another myelin‐derived axon‐repulsive molecule (Mukhopadhyay (3)et al., et al., et al., et al., et al., via activation of CSPG receptors such as protein tyrosine phosphatase σ (PTPσ) et al., et al., et al., et al., et al., et al., et al., et al., et al., via the plexin (PLXN) co‐receptor  activation of endosomes that contain ADP‐ribosylation factor 6 (ARF6) removes integrins from the cell surface; and (ii) inactivation of R‐Ras GTPases, which normally activate integrins  signalling pathway  are classical axon‐guidance molecules that are mainly produced by migrating fibroblasts, pericytes and vascular cells in the core of the scar 2+) is widely used in in vitro experiments to enhance the ligand‐binding affinity of integrins to the ECM. Divalent cations such as Ca2+ and Mn2+ interact with metal‐ion binding sites of the α integrin subunit and facilitate integrin signalling et al., et al., et al., in vivo. In addition, masking of epitopes due to integrin interactions with ECM ligands can reduce the efficiency of integrin‐binding antibodies et al., et al., et al., et al., et al., et al., The kindlins and talins are two families of intracellular proteins that bind to the cytoplasmic tail of β integrins and activate the heterodimeric receptor. Integrin activation is ubiquitous throughout the body, but the exact mechanism of the ‘inside‐out’ activation by kindlin and talin is subject to intense debate (reviewed in Meves (a)et al., et al., et al., et al. et al., et al., et al., et al., et al., in situ hybridisation and RT‐PCR studies on whole‐brain lysate demonstrated that kindlin‐2 mRNA is present in the brain, while kindlin‐1 and kindlin‐3 were not detected  enhanced the signalling of the integrins that are expressed by DRG neurons. Importantly, kindlin‐1 promoted neurite outgrowth on the axon‐repulsive substrates aggrecan and Nogo‐A et al., et al., et al., et al., Integrin‐mediated regeneration is most successful when the appropriate integrin is both present and activated. Thus, co‐overexpression of kindlin‐1 and α9 integrin forms a strong stimulus for axonal regeneration in tenascin‐C‐rich areas such as the dorsal root entry zone and spinal cord after a dorsal root crush et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Integrins are expressed in developing neurons and have essential roles in the formation of a functional nervous system. They are important for migration  (2)et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., in vitro et al., et al., et al., et al., et al., b). These neurons were able to regenerate into BDNF‐secreting cell grafts that were placed into subcortical lesions . However, as elaborated above for integrin receptors, additional interventions would be required to enhance the transport of TrkB into the corticospinal tract to promote substantial regeneration after spinal cord injury. In addition, it had been shown in hippocampal slice cultures that the activation state of TrkB correlates with axonal sprouting , neurotrophin‐3, and neurotrophin‐4. These neurotrophic factors promote neuronal survival and axonal growth and are involved in synaptic plasticity in vitro . Consistent with the absence of the receptor in the axonal compartment, corticospinal tract axons were not able to regenerate through IGF‐secreting cell grafts that were transplanted into the lesion after a spinal cord injury in vivo . Interestingly, the latter study showed that the ceruleospinal and raphespinal axons did regenerate into these grafts. We therefore hypothesise that these two descending motor pathways retained IGFRs in their axonal compartments, but the authors did not examine the receptor expression in these neurons. A recent study took an alternative approach and delivered IGF‐1 together with osteopontin into the sensorimotor cortex in order to promote corticospinal tract regeneration. Viral vector‐mediated delivery of both ligands in the cortex, but not IGF‐1 or osteopontin alone, promoted axonal regeneration approximately 1 mm beyond the lesion site after spinal cord hemisection  and has been shown to promote neuronal survival and outgrowth  overcoming the transport block of the axon initial segment and; (ii) stimulation of anterograde transport by modulation of transport vesicles; or (iii) adding axonal localisation signals to growth promoting receptors to enter the axon.Integrins are important mediators of axonal regeneration in the injured nervous system. Integrins stimulate axonal regeneration when they are activated and localised at the growth cone to interact with the ECM. In order to use receptors as potential therapeutic targets to promote axonal regeneration, the mechanisms of axonal transport and trafficking need to be better understood. The successful use of activated integrins to promote regeneration of sensory axons leading to recovery of mechano‐ and temperature sensations X.(1) Integrins are localised at the growth cone of immature and regenerating neurons and connect the extracellular and intracellular compartments of the neuron.(2) Matching the extracellular matrix environment with the appropriate integrins promotes limited axonal regeneration of mature neurons.(3) Presence of integrins in the axon correlates with the regenerative capacity of neuronal pathways.(4) Integrins participate in spontaneous axonal regeneration after peripheral nerve injuries.(5) Axon‐repulsive molecules at the lesion site of spinal cord injuries inactive integrins and thereby inhibit axonal regeneration in the central nervous system.(6) Stimulation of integrin signalling can overcome the repulsive molecules at the site of injury and promote limited sensory axon regeneration in the central nervous system.(7) Integrins become excluded from the axon during maturation of most central nervous system neurons and this correlates with the loss of the regeneration ability of mature neurons.(8) Pioneering work targeting integrins to the axons of mature neurons to promote regeneration serves as a model for other regeneration‐associated receptors that are excluded, such as TrkB and IGF‐1R.XI.This review was funded by a Nathalie Rose Barr award (NRB110) from the International Spinal Research Trust, a grant from the Medical Research Council (G1000864), an ERA‐NET NEURON grant AxonRepair (013‐16‐002) and support from the Hersenstichting Nederland, NWO, and the Laboratory for Regeneration of Sensorimotor Systems at the Netherlands Institute for Neuroscience.


Dear Editor, et al. (2018) rightly draw attention toaffordability issues in most parts of the world, and we now know that over 50% of womenundergoing IVF do not need IVF (Prognostic factors in IUI analyses is a subject both topical and of importance ifpregnancy rates in IUI are to be improved. Although the recent retrospective study(


Transcriptomics has developed into an invaluable tool in chemical hazard identification . Analysis of these genes in hepatocytes incubated with compounds not present in the above mentioned set of 162 test substances showed that at least one of these seven genes was also deregulated in the set of independent compounds.To bridge this gap, Marianna Grinberg and colleagues from Dortmund University recently published the corresponding directory of rat hepatotoxicants . LaboraCurrently, hepatotoxicity represents a major research field in toxicology (Vartak et al., 2016; Godoy e


We thank Daly-Smith et al. for taking the time to read the results of our pilot research study, describing it as an important and welcome contribution. Nonetheless, the authors argue six points against our conclusion. We contend that we addressed three of these points in our original discussion and disagree with their remaining points. Overall, their Commentary adds little to the topic of research into the Daily Mile™ that we had not already raised in our discussion. Additionally, they attribute statements to us that we did not make and ignore the raising of key issues in our original article. Given this, we stand by our original peer-reviewed conclusion that introducing the Daily Mile™ to the primary school day appears to be an effective intervention for increasing levels of moderate to vigorous physical activity, reducing sedentary time, increasing physical fitness and improving body composition, and that these findings have relevance for teachers, policy-makers, public health practitioners and health researchers. We thank Daly-Smith et al.  for takiDaly-Smith et al.  make sixDaly-Smith et al.  describeIt would have been preferable to assess both the intervention and control schools at the same time of year to avoid any seasonal impact on physical activity. However, we believe that October and March should be similar enough to allow comparison” .arison” Daly-Smith et al.  suggest Daly-Smith et al.  suggest introducing the Daily Mile to the primary school day appears to be an effective intervention for increasing MVPA and reducing sedentary time and it has measurable impacts on key aspects of metabolic health: body composition and physical fitness” .


Fungi and bacteria are the main terrestrial decomposers as they act in virtually all ecological niches  public databases (Sauget et al., Characterizing and identifying the constituents of microbial assemblages unravel surprising ways microorganisms affect ecosystems and human activities (Peay et al., Estimates on the number of fungi species vary considerably and even as many as 1.5 million species seems to be a conservative number (Hawksworth and Lücking, NL, CS, and MP proposed and conducted the discussions that led to this opinion piece. MS and RC researched the literature and drafted the manuscript. NL, CS, and MP revised the manuscript. All authors approved the final version.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.


With interest, we read the recent paper by Nigro et al. on the differential diagnosis of hypernatremia in intensive care unit (ICU) . One of