Do you find yourself teaching courses and watching the students' eyes glaze over, clearly disengaged from the class material? Are you concerned that bright young undergraduates spend too much time memorizing esoteric facts from a textbook and regurgitating them on exams rather than motivating themselves to delve deeply into scientific literature, explore the questions and issues confronting modern scientists, and seek out solutions by employing their critical thinking skills and creativity? Have you ever asked your undergraduate students how they would make 100 mL of a 10% sucrose solution and they don't know the answer? Students most certainly encounter this type of quantitative reasoning problem in their Chemistry courses, so are you surprised when transferring this highly practical skill set to analogous problems in a Biology course presents such a challenge to students? If any of these questions provokes a “yes,” you should consider offering a course that ties research and teaching together and at the same time addresses issues that are relevant to real life. By implementing such courses at UCLA, where we focus on global climate change, soil erosion and degradation, increasing numbers of antibiotic resistant bacteria, and non-sustainable farming and forestry practices for a growing human population, we have not only energized our own teaching, but also have inspired our students to become fully engaged in a scientific undertaking to contend with globally-relevant environmental issues confronting twenty-first century society.Engaging undergraduates in authentic research experiences, particularly if this immersion occurs during the first 2 years of college, is a well-documented intervention shown to increase the likelihood of students persisting in science, technology, engineering, and mathematics (STEM) majors and matriculating into post-graduate STEM degree programs . Each two-quarter series enrolls between 30 and 40 students and may be offered multiple times per year. Students are encouraged to enroll in these courses during their junior year, before they take most of their upper-division electives. This design strategy allows students to acquire experiential context for the more specialized and advanced coursework in their majors. In addition, should student participation in these course-based research experiences inspire some of them to become more interested in research, participation during their third year of college allows enough time for students to pursue an independent research apprenticeship with a faculty mentor during their senior year.An evaluation of this interdepartmental laboratory program is ongoing. According to self-report surveys given to students enrolled in the research-based courses between 2010 and 2013, students report significant gains in a variety of research skills, with gains for underrepresented minority students (URMs) significantly larger than for non-URM students in half of the categories surveyed . Furthermore, when asked to describe their post-baccalaureate plans, a majority of students cited aspirations to pursue scientific careers. These assessment results suggest that the research-based curriculum is an effective intervention in the upper-division courses for sustaining URM student enrollment in STEM courses and for promoting academic success in STEM coursework, thereby addressing major disparities in graduation rates for URM vs. non-URM students  to verify diazotrophy in addition to the 16S rRNA gene. Other students perform “trap experiments,” looking for microbes that elicit nodule formation and nitrogen fixation on various legumes. So, in addition to learning about soil community diversity, some students gain knowledge about microbial activities in this terrestrial environment through the detection of nifH or other metabolic genes whereas others directly work with plants and look for microbes that can help them grow not only via nitrogen fixation, but also through the production of auxin or siderophores or by solubilizing rock phosphate. We also spend time in our courses discussing global energy consumption and the need for developing renewable energy sources such as biofuels. Student teams try to isolate cellulase-producing microbes by screening bacteria they cultured on a medium containing carboxymethylcellulose (Teather and Wood, In our two courses at UCLA, we contextualize the students' investigations of the soil microbiome around civic-minded issues related to the plant rhizosphere. For instance, we devote time talking to students about sustainable agricultural practices: how nitrogen-fixing bacteria can be utilized as biofertilizers Vessey, , replaciWhat better way to address broader impacts on your next grant proposal than to creatively integrate your research and teaching in a way that fosters civic engagement and eco-consciousness, and at the same time supports learning and persistence of all students in STEM? Even more so, what better way for us, as educators, to be involved in major issues confronting these young people who will live in a much more crowded world than we have lived in—a world that will be looking to produce enough food and fuel for the 10 billion of us projected for 2050?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 rapid development of high-throughput techniques and accumulation of big transcriptomic data, plenty of computational methods and algorithms such as differential analysis and network analysis have been proposed to explore genome-wide gene expression characteristics. These efforts are aiming to transform underlying genomic information into valuable knowledges in biological and medical research fields. Recently, tremendous integrative research methods are dedicated to interpret the development and progress of neoplastic diseases, whereas differential regulatory analysis (DRA) based on gene coexpression network (GCN) increasingly plays a robust complement to regular differential expression analysis in revealing regulatory functions of cancer related genes such as evading growth suppressors and resisting cell death. Differential regulatory analysis based on GCN is prospective and shows its essential role in discovering the system properties of carcinogenesis features. Here we briefly review the paradigm of differential regulatory analysis based on GCN. We also focus on the applications of differential regulatory analysis based on GCN in cancer research and point out that DRA is necessary and extraordinary to reveal underlying molecular mechanism in large-scale carcinogenesis studies. In the past decade, plenty of computational methods and algorithms such as differential analysis and network analysis , 2 are pCancer is a complex disease and an effective way to study regulatory role of genes involved in cancer is to summarize them into network . It is sAlthough network analysis provides the possibility to comprehensively understand biological processes, it does increase the computational complexity. Decreasing the searching space before network analysis is necessary in high dimension data analysis. An obvious strategy of reducing the computational burden is to build a subnetwork around a given set of genes such as previously reported disease-related genes  or arounRecently, differential coexpression analysis (DCEA) increasingly plays a robust complement to DEA  and is wIn this review, we will introduce the paradigm of differential regulatory analysis (DRA) based on gene coexpression network (GCN). We also focus on the applications of DRA based on GCN in cancer research and point out that DRA is necessary and extraordinary to reveal underlying regulatory mechanism in large-scale carcinogenesis studies.Differential regulatory analysis based on gene coexpression network has been widely used in carcinogenesis regulation research and basically includes three procedures as shown in In a gene coexpression network, genes are nodes and their correlations are represented by the edges of network. Pearson correlation coefficient (PCC) is the mostly used score to measure the tendency of gene expression correlation –28. The Weighted correlation network analysis (WGCNA) , 28 is wLink-based quantitative methods in DCGL , 31 emplGaussian graphical model (GGM) is another approach to construct gene coexpression network –34. BaseSome algorithms are proposed with focus on how to infer the structure of gene correlation relationships. Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE) , 36 is aDECODE  combines the information from both differential coexpression and differential expression to set up the thresholds systematically based on a chi-square maximization .A recent GCN construction algorithm is proposed by Planar Filtered Network Analysis (PFNA) and Multiscale Embedded Gene Coexpression Network Analysis (MEGENA) , 41. AccAfter the gene coexpression network is constructed based on the transcriptomic data, regulatory information can be extracted by various regulatory analysis methods from the GCN according to research desires as shown in Another important method looking for regulatory elements is clustering method. A major goal of coexpression analysis is discovering biologically related modules or gene groups. In WGCNA, hierarchical clustering method is used to identify highly correlated gene subnetworks . SignifiAccording to topological structure of gene coexpression network, some interesting characters such as hub genes can help to explain regulatory function contained in the GCN. Connectivity in GCN presents how a gene connects to other genes and hub genes are the ones with very high level of connectivity. Hub genes are normally connections between different gene modules and should be a specific research focus for investigations into cancer-correlated gene modules. For instance, Yang et al. build gene coexpression networks based on transcriptomic and clinical data of four cancer types and discovered that prognostic mRNA genes tended not to be hub genes . They suDistinguishing different regulatory elements between different conditions such as tumor and normal tissue, or different cancer types, or even cross-species (human and mouse)  help to There are two ways to perform differential regulatory comparison between different conditions. The first way is to construct gene coexpression network based on each condition and compare the difference between constructed GCNs to extract different regulation elements as shown in Recently, differential regulatory analysis based on GCN is applied in more and more cancer studies. In the following, we give some examples of its applications and summarize advantages of this integrative method.The direct advantage of differential regulatory analysis (DRA) is that DRA is able to distinguish dysfunctional regulatory subnetworks or pathways in cancer status. For example, Jiang et al. constructed highly preserved gene ontology biological process (GO_BP) gene coexpression network and prostate cancer coexpression network by using WGCNA approach. With regulatory analysis they discovered 548 GO_BP coexpression modules and 294 prostate cancer coexpression modules. By comparing the difference of these modules, they identified 55 conserved prostate cancer coexpression modules . And theCancer is considered as a complex disease with multilevel progressing process. DRA based on GCN is able to bring light to dynamic regulatory relationships of cancer in its different progress levels. For instance, Cao et al. first constructed gene coexpression networks of normal, adenoma, and carcinoma-specific gastric carcinogenesis to decrease the searching space for potential regulatory genes . After tWith the emerging roles of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in gene regulatory networks, more and more genomic studies on miRNAs and lncRNAs are performed in cancer research aspects –58. By iFor example, Lin et al. constructed a cross-cancer miRNA differential coexpression network and identified two potential miRNA-regulated oncomodules associated with poor survival outcomes in patients . This stSince DRA based on GCN is a system-level analysis method and explores the regulatory mechanisms of diseases, it has been widely applied in medical and pharmaceutical aspects. By integrating other pieces of information such as clinical information or drug-target genes information, DRA based on GCN has more potential to contribute to theoretical base of medical and pharmaceutical researches.For example, prognostic genes are very important for cancer prognosis and treatment. By integrating survival information, Yang et al. studied the system-level prognostic genes across four cancer types by DRA based on GCN . DiscoveRegulatory analysis is always a focal point in biological research. Understanding the function of each regulatory element in biological process is fundamental and challenging. Large-scale and multilevel sequencing data provide more opportunities to reveal molecular regulatory mechanism from the systematic viewpoint. Differential regulatory analysis is designed for distinguishing the differential regulatory elements in different conditions or dysfunctional regulation specific for an abnormal condition. For example, cancer is considered as a complex genetic disease and different phonotypes in cancer embody regulatory level mechanisms. Dysfunctional regulatory elements take priority in carcinogenesis studies because of their important roles in regulation as well as their potential in cancer treatments.In the early past decade, gene expression data for specific phenotype is very limited and researchers had to use various cell lines data to construct conceptual gene regulatory networks . Then itTechnically, construction of coexpression networks as the basic starting point of differential regulatory analysis plays important and critical role in the whole investigation process. Therefore, both the data sets and the way to construct networks must be carefully examined. For example, Ballouz et al. suggest minimal experimental criteria to obtain useful functional connectivity and topology information of coexpression with microarrays greater than 20 samples and read depth greater than 10 M per sample . SelectiIn this review, we summarize the paradigm of differential regulatory analysis based on coexpression network of transcriptomic data and the applications of differential regulatory analysis based on GCN in cancer research. Differential regulatory analysis based on GCN is demonstrated as a necessary and potential tool to reveal underlying molecular mechanism in basic functional genomic research as well as practical carcinogenesis studies.


Invasions by alien plants provide a unique opportunity to examine competitive interactions among plants. While resource competition has long been regarded as a major mechanism responsible for successful invasions, given a well-known capacity for many invaders to become dominant and reduce plant diversity in the invaded communities, few studies have measured resource competition directly or have assessed its importance relative to that of other mechanisms, at different stages of an invasion process. Here, we review evidence comparing the competitive ability of invasive species vs. that of co-occurring native plants, along a range of environmental gradients, showing that many invasive species have a superior competitive ability over native species, although invasive congeners are not necessarily competitively superior over native congeners, nor are alien dominants are better competitors than native dominants. We discuss how the outcomes of competition depend on a number of factors, such as the heterogeneous distribution of resources, the stage of the invasion process, as well as phenotypic plasticity and evolutionary adaptation, which may result in increased or decreased competitive ability in both invasive and native species. Competitive advantages of invasive species over natives are often transient and only important at the early stages of an invasion process. It remains unclear how important resource competition is relative to other mechanisms . Finally, we identify the conceptual and methodological issues characterizing competition studies in plant invasions, and we discuss future research needs, including examination of resource competition dynamics and the impact of global environmental change on competitive interactions between invasive and native species. Invasions by alien plants represent a major component of global change  are invasive species superior competitors over native species; and (2) how do competitive interactions for resources between invasive and native species vary (over time) along environmental gradients? (see Glossary).Resource competition is a negative interaction between individuals associated with a requirement for shared limiting resources  resulting in a reduction in one or more fitness components at the individual or at the population level  and the spread (invasion phase) of invasive alien species, as well as in determining the magnitude and direction of the impact of plant invasions on invaded communities. Competitive advantages associated with a superior capacity to acquire resources have been regarded as a key factor responsible for the dominance of many alien species  vs. that of native subordinate or transient species  uptake in North American bunchgrass species, likely due to a differential ability to use nutrients compared to native species. Suding et al.  was reported to promote invasions by the alien tree Schinus molle in semi-arid savannas in South Africa  that are due to a capacity for early growth rather than to a superior competitive ability.Competition at the early stages of plant development associated with small differences in initial size and growth between neighboring individuals may have long-term effects on competitive interactions Weiner, . Both inImpatiens species, Skálová et al. , which are native to Eurasia and the Mediterranean region, and two native perennial grasses (Pseudoroegneria spicata and Poa secunda) that co-occur in their invasive range. They showed that native perennial grasses were subject to both intra- and interspecific competition with invasive annual species during early growth stages, but the type of competition differed among four harvests. This suggests that the relative importance of intra- vs. interspecific competition varies among harvests during the early stages of plant growth  to compete aboveground (for space and light) and belowground  , Smith et al.  prairie, while, under sub-optimal conditions, it acted as a nursing plant, facilitating the growth of other species.The potential role of dominance by native species in promoting the successful establishment of alien species has been recently emphasized , I. parviflora (less invasive) and I. capensis . They found that I. glandulifera was the strongest competitor, followed by I. parviflora, particularly under low soil moisture conditions, while I. capensis was sometimes limited by alien competitors. These findings seem to indicate that a high competitive ability is important in determining the invasion success of Impatiens species and that invading congeners may outcompete the native I. noli-tangere. Powell and Knight  and a reduced allocation to structural defenses  in invasive populations compared to native populations. Moreover, if plants in invasive populations had more intra- than interspecific neighbors, they could evolve a reduced competitive ability  that would allow the conservation of resources that would be otherwise required to compete against native species .The temporal component of competitive interactions between invasive and native species is an important topic of research in invasion ecology. Increasing evidence shows that competitive advantages of invasive species over natives may be important only in the initial phases of the invasion process  prevent plant invasions regardless of the competitive abilities of native vs. alien species; (2) may prevent invasions only in combination with competition from native species; or (3) may slow an invasion but not prevent it  may affect the establishment, spread, and persistence of alien species in invaded communities. Indirect competition includes competition for shared pollinators and apparent competition (see White et al., Apparent competition between plants occurs when one species alters the abundance or the distribution of consumers and thus the consumption of other species Holt, . More spRelatively few studies have examined the role of apparent competition in promoting plant invasions, although the interest in this type of competition has increased. There is evidence that apparent competition between alien and native species have significant negative consequences for native species (Sessions and Kelly, Allelopathy can be defined as the effect of one individual on its neighbors associated with the release of chemical compounds from roots, shoots, leaves, or flowers Rice, . The proWhile a capacity to produce chemical defenses against competitors has been viewed as a factor potentially conferring a species with a competitive advantage over neighboring species, recent evidence shows that increases in the production of allelochemicals in response to intense resource competition may substantially reduce the growth of the same species and increase their palatability to herbivores, with potential negative effects on their ability to compete for resources (Rasher and Hay, 2, and atmospheric N deposition, will affect the spatio-temporal distribution and dynamics of the resources available to plants (Wedin and Tilman, Global environmental changes, such as climate change, increasing atmospheric COCompetition experiments can provide important insights into the effects of global environmental changes on resource competition between alien and native species, although, to date, expected changes in competitive interactions among species have been mainly based on individual species responses (see Goldstein and Suding, Increasing levels of N deposition associated with anthropogenic activities are expected to favor the establishment and long-term persistence of invasive species (e.g., Dukes and Mooney, 2 are also expected to impact on resource competition between alien and native species. Evidence shows that elevated CO2 stimulates photosynthetic carbon gain and net primary production, improves nitrogen use efficiency, and decreases water use, thus removing some moisture constraints (e.g., Ainsworth and Rogers, 2, in the short-term, but their response in competitive systems could be reduced (Bazzaz and McConnaughay, Increasing concentrations of atmospheric CO3 vs. C4 species, or nitrogen-fixing vs. non nitrogen-fixing species. These changes can strongly affect the distribution and dynamics of soil nutrients and other resources (e.g., Vitousek et al., Tamarix (Vitousek and Walker, There is strong evidence that many invasive species are capable of altering the levels of available resources in invaded ecosystem (e.g., Vitousek et al., Invasive species may also alter the soil biota through plant-soil feedbacks (e.g., Kulmatiski et al., Changes in the availability of resources associated with plant invasions may thus create conditions that may either increase or decrease the competitive ability of invasive species vs. that of native or other alien species. How these changes will affect resource competition between alien and native species is a key to improving our understanding of the long-term implications of plant invasions on native communities. Moreover, such changes could create conditions that facilitate secondary invasions, i.e., the establishment of other alien species in a community (e.g., Gioria et al., Future research studies must address a number of deficiencies that have characterized many competition experiments in plant invasion ecology and that might have hindered our capacity to predict the role of resource competition in plant invasions. Throughout this review, we have pointed out a number of research needs on the role of resource competition in plant invasions, including that for more direct measurements of the competitive ability of invasive and native species (see also Trinder et al., Another issue characterizing competition studies on plant invasions is that many pair-wise competition experiments have compared the competitive ability of alien and native species possessing contrasting life forms, such as annuals vs. perennials (Claassen and Marler, Resource competition is a dynamic process (Trinder et al., Interpreting the outcomes of resource competition strongly depends on the way competition is measured (Goldberg et al., Phylogenetic and niche differences between alien and native species may confound the effects of resource competition and should be accounted for when predicting the outcomes of resource competition among species. Phenological differences between alien and native species should also be accounted for when examining the role of resource competition in plant invasions, as they may strongly affect competitive interactions, particularly at the early stages of plant development, and could explain why some invasive species may not be strong competitors if they can take advantage of temporal windows of opportunity when competitive interactions are weak or non-existent Figure .Coevolutionary responses among competing plants have been generally neglected (Leger and Espeland, Future studies should also examine more extensively how clonal integration, i.e., resource sharing among interconnected ramets, or plant parts (see Glossary; e.g., Alpert and Mooney, It is beyond the scope of our review to propose a detailed sampling framework or to describe in detail the drawbacks and advantages of experimental designs for assessing the importance and intensity of resource competition between alien and native species (see Trinder et al., Resource competition has long been regarded as a major determinant of the successful establishment and spread of alien species and their long-term persistence in invaded communities, although its importance relative to that of other mechanisms remains unclear. As resource competition is a dynamics process, its role in plant invasions will inevitably change over time, not only due to changes in available resources associated with disturbances, global environmental changes, or changes promoted by the invaders themselves, but also due to plastic responses and evolutionary changes that may occur during invasion processes in both invasive and native species. In this review, we highlighted the most pressing research needs in this field and described a range of factors that may confound our capacity to determine the importance of resource competition in plant invasions, including phenological differences resulting in competition avoidance, niche and fitness differences, phylogenetic relatedness, recruitment limitation, indirect competition, or allelopathy. Improving our understanding of the role of resource competition in plant invasions and its dynamics does not only represent a key ecological question but is essential to predicting the long-term impacts of plant invasions and of how they may interact with other global environmental changes.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.


The effects of aging on rehabilitation of aging-related diseases are rarely a design consideration in rehabilitation research. In this brief review we present strong coincidental evidence from these two fields suggesting that deficits in aging-related disease or injury are compounded by the interaction between aging-related brain changes and disease-related brain changes. Specifically, we hypothesize that some aphasia, motor, and neglect treatments using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in stroke patients may address the aging side of this interaction. The importance of testing this hypothesis and addressing the larger aging by aging-related disease interaction is discussed. Underlying mechanisms in aging that most likely are relevant to rehabilitation of aging-related diseases also are covered. In the past few years, new modalities have become available to manipulate activity in specific brain areas during rehabilitation. Primary among these intervention modalities are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Recent studies indicate that these modalities can be used to enhance performance in motor or language tasks in stroke patients , followed by a short discussion of stroke and aging. Subsequently, we present two examples in stroke rehabilitation where data suggest that intervention effects may be the result of addressing an aging-related phenomenon. Then, we will expand our discussion to other cognitive processes and aging-related diseases, and finally we discuss the implications for rehabilitation research in older persons.In this brief review of aging and rehabilitation, we present evidence for a different viewpoint: in many instances, these interventions may be successful because they address the interaction between an aging-related disease state and normal aging-related changes in brain function While rTMS and tDCS both can increase or decrease cortical excitability in the short run and help to remodel cortical systems in the long run, they do so by quite different mechanisms. While we discuss the underlying neural effects of these techniques later in this paper, a brief introduction is appropriate at this point. Transcranial magnetic stimulation (TMS) passes electrical current through a coil to create a brief magnetic field that penetrates the skull and induces an electrical current orthogonal to the magnetic pulse in underlying brain tissue. This current stimulates neurons in the target cortex, causing them to fire. In rTMS, stimulation is repeated in regular patterns. Low frequency rTMS reduces cortical excitability . For cathodal tDCS, the cathode is placed over the target cortex. At a cellular level, tDCS modifies the transmembrane potential by forcing the displacement of intracellular ions which cancel the generated intracellular field and thereby modify the spike firing probability  to treat language and motor disorders after stroke have become increasingly prominent in the rehabilitation literature. Stroke is a disease primarily of older persons. The risk of stroke doubles for each decade of life between the ages of 55 and 85, and age is considered a risk factor for stroke  The first consideration involves the use of single- vs. paired-pulse TMS. In single-pulse TMS Figure , the pulA receptors, which are ionotropic. Inhibition measured by paired-pulse paradigms at long intervals (tens of milliseconds) and silent period after a single pulse are mediated by GABAB receptors, which are metabatropic (see discussion below). (3) The inhibition can be measured while the muscle is at rest, during an isometric contraction, or prior to movement of the target muscle.iSP measures transcallosal (interhemispheric) inhibition, cSP measures intrahemispheric inhibition. In paired pulse TMS Figure , a pulseA receptors and increased excitability of cortical neurons close to experimentally induced ischemia  stroke survivors (mean age = 54.9 years) results in improved reaching, reduced amplitude of iSP, and reduced duration of cSP in the affected triceps , these data indicate a need to incorporate age into models of interhemispheric inhibition after stroke. We do not question that the activity in the unaffected hemisphere during motor responses of the affected hand may be detrimental to movement initiation, accuracy, and speed. However, we urge reconsideration of the concept that over-activity in the unaffected hemisphere is exclusively, or even primarily due to mechanisms emerging from stroke.Specifically, recent research in aging has shown that activity in motor cortex (M1) ipsilateral to a moving hand is suppressed in neurologically normal younger adults but increased in neurologically normal older people. Using functional magnetic resonance imaging (fMRI), McGregor et al.  found thB receptor agonists  and right M1 BOLD responses during movement of the right hand showed a negative correlation with VO2max. These correlations were not present for younger adults  are correlated with changes in behavior (dexterity), suggesting that the physiological changes have consequences in terms of motor performance. Given the fact that decreasing cortical excitability in the intact M1 of stroke patients with low-frequency rTMS or cathodal tDCS improves motor performance and/or response to therapy, we hypothesize that the loss of inhibition of M1 ipsilateral to a moving hand due to aging has a synergistic effect with stroke, increasing motor disability in the affected hand beyond what stroke-related damage does. Further, we hypothesize that reducing cortical excitability in contralesional M1 as an intervention (with rTMS or tDCS) is addressing, at least in part, the aging component of an aging by disease interaction in stroke.Understanding mechanisms underlying loss of cortical suppression in aging is critical for developing interventions to address it. The most relevant candidate neurotransmitter system to explain the differences shown between age groups is the GABAergic system. GABA is the dominant inhibitory neurotransmitter system within the central nervous system and has powerful effects on cortical activity  BOLD responses are indicative of cortical suppression  receptors. GABAB receptors have been implicated as a primary mechanism in the SP described above because the SP is prolonged in a dose-dependent manner by agents that facilitate GABAB transmission  It is likely that aging × aging-related disease interactions affect more than just motor and language functions. (2) Aging-related processes probably affect patients who have disease and injuries other than stroke. (3) Reduced cortical inhibition is likely not to be the only aging-related process that interacts with injury or disease. In addition to amyloid deposits, for example, deterioration of white matter in aging  makes the electrodes suited to delivering stimulation to a region of cortex as opposed to a specific cortical location. Most investigators have assumed they are stimulating cortical regions directly under these electrodes. However, Datta et al.  Broca’s area/left frontal cortex  An age-matched control group must be used for comparison to stroke patients to determine if the underlying mechanisms demonstrated by stroke patients are associated with their neurologic insult; (2) A younger control group must be used for comparison to stroke patients and to the age-matched control group to determine if the underlying mechanisms are related to age as opposed to stroke. For example, if we wanted to know if an index of inter-hemispheric inhibition of the unaffected on the affected M1 were age or stroke related, we would need to include the stroke group, an age-matched control group, and a young control group. Use of multiple platforms to measure various aging related phenomena  also should be considered.Using both old and young control groups also can be used for assessing brain stimulation as a potential treatment for language, neglect, or motor problems. For example, Wierenga et al.  found thB or GABAA receptor activity, respectively  because the close parallels with recent aging research raise important questions regarding the role of aging in rehabilitation of aging related diseases. However, it is appropriate to consider other means of affecting the aging component in rehabilitation of aging-related disease. For example, aerobic exercise and the resultant levels of increased cardiovascular fitness have proven to be one of the most robust interventions to improve cognition and enhance related brain activity in older adults, and it also appears to have protective effects against developing neurodegenerative diseases  were 60 years of age or older. By 2050, the number of Americans of this age will nearly double to approximately 112 million (25.5% of the population; Administration on Aging, 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.


Asthma is a chronic inflammatory disease of the airways that affects a growing number of children and adolescents. Inhaled corticosteroids (ICS) are the mainstay of treatment in persistent asthma, with a stepwise approach to increasing doses of ICS depending on asthma severity and control. ICS have known local and systemic side effects, of which adrenal suppression is still under-recognized. The latter is associated with chronic exposure and higher doses, although it has rarely been reported in children receiving low doses for a short period of time. The Canadian Society of Allergy and Clinical Immunology (CSACI) therefore recommends that physicians screen for adrenal suppression in children receiving high doses for more than 6 months and to consider screening those on medium dose if the risk is deemed higher by factors that increase an individual’s systemic corticosteroid exposure. Morning serum cortisol level can be used as a screening tool and abnormal results or normal results with a high index of suspicion should be confirmed with low-dose ACTH stimulation tests. Asthma affects about 10% of the Canadian population, and 50-80% of children affected develop it before the age of 5 years [Topical anti-inflammatory therapy has become the main modality of asthma control therapy, in children, adolescent, and adults, with inhaled corticosteroids (ICS) being the preferred choice after four decades of clinical experience. As stated in the Canadian Thoracic Society Asthma Management Continuum 2010 Consensus, “there is robust evidence confirming that ICS therapy is effective at reducing asthma symptoms, improving health-related quality of life, improving lung function, decreasing airway hyper-responsiveness, controlling airway inflammation, reducing the frequency and severity of exacerbations, and reducing asthma mortality. Most patients can achieve asthma control using relatively low doses of ICS, which will produce maximum or near-maximum clinical benefit, with minimal risks of long-term adverse effects [A daily ICS regimen is recommended for the treatment of persistent asthma starting with low-dose monotherapy for most children and adolescents, with a step-up approach to medium and high-dose ICS  depending on asthma severity and control. It is well established that the higher the daily dosage, the larger the probability of side effects will be ,3. In reBioavailability, determined by dosage, device used, particle size, lung versus upper airway deposition, proportions of inactive pro-drug versus active drug at mucosal surfaces, as well as serum protein binding, all influence the probability of experiencing side effects from the use of ICS .Local ICS side effects include oral candidiasis and dysphonia, usually prevented by rinsing after inhalation and use of a spacer in children on metered dose inhalers. Systemic side effects include adrenal suppression, decreased bone mineralization, and growth suppression . Of thesLipworth et al  reviewedBased on these findings, the Canadian Society of Allergy and Clinical Immunology (CSACI) recommends that all children and adolescents who are receiving a high dose of ICS as defined by the Canadian asthma guidelines ,3 for 6 The preferred initial method of screening for adrenal suppression is to measure morning serum cortisol level in children over 2 years of age who have established a circadian rhythm of cortisol secretion, and this test is readily available to physicians in Canada. Normal values vary per laboratory. For an accurate measurement, the morning serum cortisol level should be obtained following the specifications of your local laboratory.Of note, a potential pitfall of this screening tool is that its sensitivity is about 60%, so normal values do not rule out HPA axis suppression . Therefo2/day) might be necessary until the morning serum cortisol returns to normal, usually after 6 to 12 months. In those in which the diagnosis was made by stimulation testing because the morning serum cortisol was normal, the endocrinologist should assess when the child is no longer considered to have adrenal suppression and no longer needs physiologic replacement therapy or stress precautions [Patients with adrenal suppression should be managed in conjunction with an endocrinologist. Hydrocortisone at a physiologic dose . ICS may be increased to medium dose in children 6–11 years old or LABA added in those >12 years of age if asthma is severe or poorly controlled. This step up should be done only after assessing that lack of control is not due to inadequate treatment adherence, poor inhaler technique, or co-morbidities such as uncontrolled upper airway disease, or that the diagnosis is other than asthma. In patients failing to respond to escalation, consultation with an asthma specialist is strongly recommended.Systemic side effects of inhaled corticosteroids include HPA deficiency leading to adrenal suppression, usually associated with high doses and long treatment duration. It has been rarely reported in children receiving low or medium dose ICS for a short period of time..Screening for adrenal suppression is recommended in children taking high dose ICS  for more than 6 months. Consideration should be made to screen those on medium dose  if the risk is deemed higher by factors that increase an individual’s systemic corticosteroid exposure. High-risk factors include ICS dose in the higher end of the range, prolonged duration of treatment at such dose, concomitant use of nasal and topical corticosteroids, recent or frequent short courses oral steroids, high level of adherence to therapy, and smaller body mass for ageAssessment of morning serum cortisol is readily available but has poor sensitivity. Abnormal results or normal results with high index of suspicion should be referred to endocrinologist and adrenal suppression confirmed with a low-dose ACTH stimulation test.When adrenal suppression is confirmed, children should be managed in conjunction with a pediatric endocrinologist. Oral physiologic corticosteroid replacement therapy should be prescribed and written instructions for stress corticosteroid dosing should be provided until the adrenal suppression resolves. The use of a medical identification tag is advised until the adrenal suppression resolves.


Since the mapping of acoustic variability is language-specific, these categories must be learned from experience. Thus, understanding how, in general, the auditory system acquires and represents categories can inform us about the toolbox of mechanisms available to speech perception. This perspective invites consideration of findings from cognitive neuroscience literatures outside of the speech domain as a means of constraining models of speech perception. Although neurobiological models of speech perception have mainly focused on cerebral cortex, research outside the speech domain is consistent with the possibility of significant subcortical contributions in category learning. Here, we review the functional role of one such structure, the basal ganglia. We examine research from animal electrophysiology, human neuroimaging, and behavior to consider characteristics of basal ganglia processing that may be advantageous for speech category learning. We also present emerging evidence for a direct role for basal ganglia in learning auditory categories in a complex, naturalistic task intended to model the incidental manner in which speech categories are acquired. To conclude, we highlight new research questions that arise in incorporating the broader neuroscience research literature in modeling speech perception, and suggest how understanding contributions of the basal ganglia can inform attempts to optimize training protocols for learning non-native speech categories in adulthood.Listeners must accomplish two complementary perceptual feats in extracting a message from speech. They must discriminate linguistically-relevant acoustic variability and generalize across irrelevant variability. Said another way, they must  This is an example of categorization, in that potentially discriminable sounds come to be treated as functionally equivalent classes defined by relevant features . This contrasts to the general approach in speech categorization research, which has focused largely on learning-induced category representations occurring at the sensory level  and the nucleus accumbens . The dorsal and ventral striatum receive input from the cerebral cortex and send projections to the output nuclei of the basal ganglia, which include the globus pallidus and the substantia nigra pars reticulata   for the categories, one's actions are shaped to respond differently to these sound categories, thereby assigning distinct behavioral significance to the sounds.Using fMRI, Tricomi et al.  demonstrIt is notable that non-native speech category learning in adulthood occurs with directed categorization training, but learning gains are relatively modest even across multiple weeks of extensive training  vs. integration of dimensions  that define categories is achieved by distinct, competitive learning systems  in inducing perceptual plasticity and learning regardless of the direct relevance to the perceptual stimuli used in the task . For example, listening to speech sounds activates both auditory regions  and motor regions involved in speech production  is tuned to exhibit a selective improvement in processing category-relevant over -irrelevant dimensions  while simultaneously parsing continuous speech input. In addition, speech exposure often occurs within complex visual scenes for which there are multiple potential referents, creating additional learning challenges (Medina et al., category learning and generalization. Nonetheless, although research on task-irrelevant perceptual learning does not yet converge with the learning challenges of non-native speech category learning, it does provide insight in the learning systems that may be engaged to modify sound perception. It may be fruitful to try to bridge this gap in future research.A different line of research has suggested that implicit, task-irrelevant perceptual features of rewarded stimuli can be learned with passive exposure via a diffuse dopamine signal (Seitz and Watanabe, The Wade and Holt  videogamThe basal ganglia are a very complex and intricate neural structure, consisting of multiple sub-structures that interact with most cortical areas through diverse connections. The structure has been highly implicated in motor functions. However, general learning studies outside of the speech/auditory domain have revealed its contribution to cognitive functions, particularly in learning from external feedback to form goal-directed and procedural behaviors as well as learning visual categories.In the domain of speech category learning and elsewhere, research commonly uses explicit feedback-based tasks to induce effective learning. Although this type of task engages the basal ganglia system during learning, and is known to be effective for acquisition of non-native speech categories (McCandliss et al., The topics of speech perception and learning, and basal ganglia-mediated category learning, have been largely studied independently. Speech perception, once considered a “special” perceptual system, has only recently begun to be studied in a manner that fully incorporates general cognitive/perceptual learning research on the development of perceptual representations. On the other hand, studies of basal ganglia function with regard to category learning have emphasized understanding of the process of learning category-relevant decisions rather than learning-related changes in perceptual organization. However, these separate lines of research share commonalities. We have attempted to argue that there is great potential in bridging efforts to understand speech perception and learning with general cognitive neuroscience approaches and neurobiological models of learning.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.


A number of influential theories posit that visual awareness relies not only on the initial, stimulus-driven  sweep of activation but also on recurrent feedback activity within and between brain regions. These theories of awareness draw heavily on data from masking paradigms in which visibility of one stimulus is reduced due to the presence of another stimulus. More recently transcranial magnetic stimulation (TMS) has been used to study the temporal dynamics of visual awareness. TMS over occipital cortex affects performance on visual tasks at distinct time points and in a manner that is comparable to visual masking. We draw parallels between these two methods and examine evidence for the neural mechanisms by which visual masking and TMS suppress stimulus visibility. Specifically, both methods have been proposed to affect feedforward as well as feedback signals when applied at distinct time windows relative to stimulus onset and as a result modify visual awareness. Most recent empirical evidence, moreover, suggests that while visual masking and TMS impact stimulus visibility comparably, the processes these methods affect may not be as similar as previously thought. In addition to reviewing both masking and TMS studies that examine feedforward and feedback processes in vision, we raise questions to guide future studies and further probe the necessary conditions for visual awareness. The exact mechanism by which visual awareness arises and the neural circuits involved in generating this experience are greatly debated . HoweverThe visual system has abundant anatomical feedforward and feedback connections that are organized in a hierarchical manner . InitialThe role of feedback processes in vision as well as when and how they are initiated is still debated. Feedback amplifies and focuses activity of neurons in lower visual areas , 2001. HIt has been a challenge to establish the exact timing of these neural events because they are dependent on stimulus properties, species-specific neural architecture, and experimental procedures. For example, because magno and parvo cells exhibit distinct spatial frequency and contrast sensitivities , the phyIt has been argued that some natural stimuli, such as real-world objects, animals, or scenes, can be perceived on the feedforward sweep; that is, observers can successfully identify such stimuli with presentation times that are too short to allow for feedback . In thesNumerous theories and methods of visual masking exist, and the nuances of these models are beyond the scope of this review. Most models fit within the general framework of feedforward and feedback processing that we discuss in this paper. However, for completeness sake, we direct an interested reader to several excellent reviews that discuss alternative methods and theories of visual masking .Visual masking occurs when perception of one stimulus, a target, is reduced by the presence of a second stimulus, a mask. The strength of masking is quantified as the reduction in the visibility of some aspect of the target . In forward masking the mask stimulus precedes the to-be-discriminated target; in backward masking the mask follows the to-be-discriminated target. Metacontrast is a specific case of backward masking in which spatially contiguous but non-overlapping stimuli are used. Because the target and mask do not overlap spatially, and thus do not stimulate the same retinal cells, any interaction between the target, and the mask must occur primarily at the cortical level. In line with this idea, target visibility is strongly impaired under dichoptic presentation conditions in which target and mask stimuli are presented separately to each eye . Here, tFigure 1). The exact SOAs of optimal masking vary from study to study due to differences in experimental parameters and criterion the subject is asked to adapt . This pattern of results indicates that the strongest interaction between target and mask neural events occurs when they are separated by several tens of milliseconds rather than immediately.By varying the stimulus onset asynchrony (SOA) between the target and the mask one can track the change in the visibility of the target with respect to the onset of the mask. Metacontrast typically yields U-shaped target visibility functions . Several studies have also reported an additional and very late post-stimulus TMS effect at 200 to 280 ms after the onset of the stimulus . In other words, visual and TMS masking paradigms impair stimulus visibility at comparable time windows, suggesting that they affect the same visual process(es) that are critical for visual awareness  while the early neural response is generally unaffected . SimilarElectroencephalography recordings with humans reveal similar findings to those of single-cell recording studies. With this mechanism of masking in mind let us return briefly to studies that employ overlapping target and mask stimuli to make inferences about feedforward and feedback processes and their contribution to visual awareness. As discussed earlier, stimuli that overlap in space activate identical cells along the visual processing pathway allowing masking to occur due to sensory signal integration at pre-cortical levels. Because these studies typically employ pattern masks, successful discrimination of natural stimuli under ultra-rapid presentation conditions  likely indicate poor integration masking rather than scene processing that does not require feedback; that is, fairly high target accuracy even at the shortest SOAs  may indiThe neural mechanisms behind TMS-induced reduction of stimulus visibility are less clear, due primarily to unknown variation in retinocortical transmission time. If we accept a retinocortical transmission time of 60 ms , then thTo directly test similarities and differences between metacontrast and TMS, Although the timing of the TMS and visual masking effects obtained by The hypothesis that the 100 ms TMS suppression window may reflect interference with (some of the) feedforward in addition to (multiple recurrent) feedback processes  is only If post-stimulus TMS over EVC at around 100 ms interrupts solely feedback processes, we would also expect similar  effects in TMS paradigms; that is, we would expect to obtain priming from a TMS-masked target. Alternatively, if post-stimulus TMS also interferes with (some of the) feedforward processes during this time window, performance on tasks that rely on feedforward activity should be impaired; that is, we would expect priming to be diminished when the target is suppressed by TMS. Only a handful of studies have investigated this hypothesis to date, but they all show that priming is either reduced  or entirIt is difficult to draw clear conclusions about feedforward and feedback processes from these studies not only because there are only a few of them, but also because the experimental procedures used differ among the studies. TMS stimulation parameters  should be systematically explored in the priming task as they have been shown to differentially affect performance in other paradigms . AdditioIn summary, although it has been previously argued that the 100 ms post-stimulus window reflects TMS interference with feedback processing in EVC, data from the newest studies suggest that the classical TMS window of suppression might in fact encompass both the feedforward and feedback processes, with lower SOAs tapping into the feedforward and later SOAs tapping into the feedback activity . Hence, Figure 2). In paracontrast strongest suppression of target visibility is obtained at SOAs around -170 to -100 ms and -10 ms .As in forward visual masking paradigms, TMS can also be applied before the onset of a visual stimulus. Pre-stimulus TMS impairs target visibility at a range of SOAs spanning from -80 to -10 ms , 2014. IBehavioral and especially neural effects of paracontrast are much less studied than those of metacontrast. This is likely due in part to the fact that paracontrast produces much weaker suppression than metacontrast . Single-The neural consequence of the pre- and early post-stimulus TMS reduction of visibility is under question. Post-stimulus effects of SOAs up to 60 ms have been difficult to replicate consistently ,b. MoreoFigure 2). Of course, these conclusions critically depend on actual retinocortical transmission time. If one accepts that the backward masking effects of TMS and visual masks are comparable, then it is tempting to conclude that paracontrast and forward masking effects with TMS tap into the same visual mechanism of processing, this time interference with the feedforward signal  have been shown to modulate neural responses in striate and extrastriate visual areas . The FEFAwareness is an emergent property of the brain and arises amidst other equally complex processes. Therefore, trying to pinpoint the neural correlate of consciousness (NCC) or more specifically of visual awareness may be misleading. For instance, there may be prerequisite conditions for the “true” NCC (or NCC-proper) to emerge as well as events that consistently arise as a result of awareness. The distinctions among these three NCCs have been discussed eloquently and in detail elsewhere e.g.,  and are Ongoing alpha oscillations (8-12 Hz) not only reflect a brain state that has been implicated in visual awareness, but they are also modulated by TMS. Visibility of a masked target in metacontrast fluctuates as a function of power and phase of occipito-temporal EEG alpha , 2012. IInterestingly, even when alpha power is high there appear to be mechanisms that modulate awareness. Specifically, stimulus visibility varies as a function of alpha phase and is observed only under high alpha conditions , 2012. FFigure 3). Of course, it is equally likely that the target appears during the excitatory phase of alpha, resulting in poorer masking and better detection of the target. Such a mechanism could explain why metacontrast masking rarely occurs on 100% of trials. Alpha phase alone cannot account for backward masking more generally, however, because alpha power is low when a study participant is fully engaged in the task. In this case, phase has little to no effect on stimulus visibility, yet metacontrast masking still occurs during low alpha power states, albeit at a reduced rate compared to trials occurring during high alpha power states  fall within the half cycle of alpha. Indeed, the timing is such that if the target appears in an inhibitory phase of alpha, the mask will fall in the excitatory phase, potentially increasing the chances that the feedforward signal from the mask will interfere with the target  and post-stimulus TMS masking effects have been thought to occur due to interference with feedback processes that are required for visual awareness, while forward visual (paracontrast) and pre-stimulus as well as early post-stimulus TMS effects have been proposed to reflect interference with the initial feedforward activity. Recent empirical evidence, however, suggests that the parallels between metacontrast and TMS masking might not be as straightforward as previously thought. While metacontrast occurs due to the mask interfering with feedback processes of the target, post-stimulus TMS possibly interrupts not only the feedback but also (some of the) feedforward processes. Additionally, forward masking (paracontrast) was thought to reflect interference with feedforward processing, but recent work looking at alpha oscillations raises the possibility that pre- and early post-stimulus TMS influence stimulus visibility by affecting the brain state prior to target onset. Future research should also inform the involvement of feedforward activity in post-stimulus TMS masking window and elucidate how and why this method of masking differs from that of metacontrast. Additionally, assessing the exact retinocortical transmission time for visual stimuli and specific time windows of suppression with TMS and visual masks should help disentangle feedforward and feedback contributions to visual processing in these paradigms. Finally, exploring the contributions of oscillatory alpha power and phase will help establish the necessary and sufficient conditions to visual awareness by parsing out prerequisites from NCC-proper.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.


The mouse haploid ES cells can also contribute to germlines of chimeras. Moreover, the mouse androgenetic haploid ES cells can produce fertile progenies after intracytoplasmic injection into mature oocytes, and the mouse parthenogenetic haploid ES cells can also achieve this by substitution of the maternal genome, albeit at a lower efficiency. These distinct features of mammalian haploid ES cells empower themselves not only as a valuable tool for genetic screening at a cellular level, but also as a new tool for genome-modified animal production and genetic studies at the animal level. Here we review the current progress on mammalian haploid ES cell research, describe in detail their characteristics, and discuss their potential applications. These achievements may provide a new but powerful tool for mammalian genetic studies, and may also shed light on the some interesting questions regarding genome ploidy maintenance and genomic imprinting.In mammals, all somatic cells carry two sets of chromosomes while haploids are restricted only to gametes and are occasionally found in tumors with genome instability. Mammalian haploid embryonic stem (ES) cells have recently been established successfully in mice and monkeys, from either parthenogenetic or androgenetic haploid embryos. These haploid ES cells maintain haploidy and stable growth during extensive  Establishing mammalian haploid cell lines for genetic screening and to study recessive traits in mammals would therefore be of great value.Haploid cells are optimal tools for genetic screening due to their single-set chromosome feature. Compared with using diploid cells, it is much easier to use haploid cells to produce homozygous mutants that are essential for study of recessive traits. Haploid cells only exist naturally in yeast and bees  and somein vitro[Since the 1970s, large efforts have been made to generate haploid embryos in the mouse, such as derivation of haploid mouse embryos by different strategies -5. The sin vitro,9, and win vitro but also held pluripotency like conventional ES cells [in vitro, and hold pluripotency as revealed by the expression of pluripotent markers and differentiation into three germ layers including the germline. Importantly, the mammalian haploid ES cells excelled themselves not only as efficient genetic screens at a cellular level, but also in the production of gene-modified animals by substituting the gamete genome at the animal level.The first successful derivation of vertebrate haploid cells came in 2009 with the establishment of haploid ES cells in Medaka fish, which not only maintained haploidy during cell culture ES cells . After tHere, we review the characteristics of mammalian haploid ES cells with a focus on their pluripotency and epigenetic features, and further discuss the potential application of these cells in recessive gene screens and transgenic animal model production.in vitro, with no auto-diploidization. But mammalian haploid ES cells were weaker in a haploid state than fish haploid ES cells  presenting defects in pre-implantation development . Accordiin vivo experiment, Li and colleagues derived epiblast-like haploid stem cells from ahES cells by differentiation in vitro, which showed many features of primed-state stem cells and suggested that haploid stem cell lines could be established beyond the naïve ES cell state [in vitro and teratoma in vivo containing three germ layers. Taken together, both mouse and monkey haploid ES cells could self-renew with an intact haploid genome and a pluripotent state  stimulus activation, the genome of the donor cell undergoes a fast demethylation process accompanied with reprogramming. Around 5 to 6 hours later, these reconstructed embryos would form a paternal pseudo-pronucleus and a maternal pronucleus, which were quite similar to the fertilized zygotes. Full-term pups could be generated by transferring these embryos back to the uterus of pseudo-pregnant mice. Most of the pups could develop to adulthood and give birth to the next generation normally, but some newborn pups generated by ICAI assay died shortly after birth because of developmental retardation, which might be due to an abnormal imprinting state in donor ahES cells. Through loss of imprinting in some imprinted genes during long-term culture in diploid ES cells [Considering the gamete origin of haploid ES cells, they may maintain parent-specific genome imprints that are essential for normal development, raising the potential to use haploid ES cells to function as gametes supporting embryonic development. Yang and colleagues  and Li aES cells , a simil2) and transferred them back to pseudo-pregnant mice; and, finally, live mice were produced by this process and could give birth to the next generation, although the efficiency was low [Equally, the phES cells that inherit oocyte genomes could support development by substituting maternal genomes of fertilized zygotes. Wan and colleagues proved this through a proof-of-principle experiment: first, they injected one sperm head into an enucleated oocyte; second, they performed intracytoplasmic phES cell injection; third, they activated these reconstructed embryos by chemical stimulus .Recent remarkable work showed that reversible gene trap collection was generated in the human near-haploid cell line KBM7, which empowered genetic screening in humans . This stHaploid ES cells have made great progress in mammalian genetic studies. They serve as a valuable tool not only at a cellular level in genetic screens but also at an animal level in transgenic animal production compared with conventional diploid ES cells. However, before being widely used in gene function research and drug selection, there are still some problems that need to be solved in haploid ES cells. The mechanism of genome ploidy maintenance in haploid ES cells is unclear, so all of the haploid ES cells have to be enriched by FACS. Determining the very factors driving diploidization of haploid ES cells is critical for us to find proper chemical compounds that may maintain haploidy in routine culture instead of the Hoechst 33342 staining and FACS method that may compromise the developmental efficiency of haploid ES cells.Moreover, deriving haploid cells in other species and other cell types is also essential. The generation of monkey phES cells suggests that haploid ES cells are also tolerated in primates, and thus it is valuable to derive human haploid ES cells in the future. Also, although monkey haploid ES cells should be useful in primate gene function research and recessive phenotype analysis, whether they can function like gametes as mouse haploid ES cells is unknown. Addressing this problem may provide insight into the assisted reproduction technology in humans through haploid ES cells.Finally, whether differentiated haploid cells could be obtained and maintained is also an interesting point. We need to determine in the future whether the haploid status could be established in a somatic state rather than just in a pluripotent state.ahES: androgenetic haploid embryonic stem; ES: Embryonic stem; FACS: Fluorescence-activated cell sorting; ICAI: Intracytoplasmic androgenetic haploid embryonic stem cell injection; phES: parthenogenetic haploid embryonic stem.The authors declare that they have no competing interests.


Introduction: With a renewed emphasis on evidence-based risk sensitive investment promoted under the Sendai Framework for Disaster Risk Reduction 2015-2030, technical demands for analytical tools such as probabilistic cost-benefit analysis (CBA) will likely increase in the foreseeable future. This begs a number of pragmatic questions such as whether or not sophisticated quantitative appraisal tools are effective in raising policy awareness and what alternatives are available.Method: This article briefly reviews current practices of analytical tools such as probabilistic cost-benefit analysis and identifies issues associated with its applications in small scale community based DRR interventions.Results: The article illustrate that while best scientific knowledge should inform policy and practice in principle, it should not create an unrealistic expectation that the state-of-the art methods must be used in all cases, especially for small scale DRR interventions in developing countries, where data and resource limitations and uncertainty are high, and complex interaction and feedback may exist between DRR investment, community response and longer-term development outcome. Discussion: Alternative and more participatory approaches for DRR appraisals are suggested which includes participatory serious games that are increasingly being used to raise awareness and identify pragmatic strategies for change that are needed to bring about successful uptake of DRR investment and implementation of DRR mainstreaming. These questions are particularly germane in the context of developing countries where data and resource limitations, computational needs and uncertainty are high, and complex interaction and feedback may exist between DRR investment, community response and longer-term development outcome.,per se is unlikely to help. While CBA has been frequently required by national and international bodies, available evidence suggests this has led to limited learning during project appraisal and implementation‘DRR investment saves’ is hardly a new story: good technical evidence exists within developed countries The true utility of appraisal methods such as CBA will likely be realized when it is used for tangible policy and investment decisions rather than mere awareness-raising. However, there are a number of practical challenges for such tangible application in developing countries. The lack of local capacities to collect and analyse hazard-, exposure- and vulnerability information is a major issue: whether downscaling efforts are made to climate hazard estimations or national average parameters are used to construct particular cost estimates, these will all contribute to increasing uncertainty bounds, and making proper sense of such uncertainty becomes a big challenge. Moreover, as these efforts require highly sophisticated analytical skills, which are often handled by external consultants, thereby removing the process of evaluation from community deliberation and learning. Methods such as CBA can be conducted in a participatory manner Given the complexity and uncertainty involved, it is unlikely that such a sophisticated approach will be appropriate for all cases, especially for small scale DRR project appraisal in developing countries. Missing reliable past disaster damage and loss estimates, probabilistic assessment of community-based interventions often rely on local knowledge: the establishment of baseline risk from annual to 2-5 year events may be feasible based on local residents’ recollection, however such methods quickly become infeasible for higher return period events such as 100 or 500 year events that are needed to accurately estimate the risk of extremes.Furthermore, these issues are compounded when the appraisal is required to integrate the future impact of climate risk, which is particularly uncertain at the local scale. This requirement may be understandable when donor funding is extended under climate change adaptation. However, when such demands are made on tools such as probabilistic CBA, it adds a further layer of uncertainty on top of the existing hazard variability and local exposure and vulnerability dynamics which themselves are often poorly understood. Even in ideal circumstances, state-of-the art risk assessments are limited int their ability to offer robust future forecast, since the further they need to project into the future, the larger the uncertainty bounds become for hazards, exposure and vulnerability. Finding meaningful interpretations therefore becomes progressively difficult.In light of these practical constraints, communities may instead use more locally appropriate methodologies to raise awareness and to plan for improved DRR practice in the context of climate change. Practitioners may raise local awareness regarding the effectiveness of 'soft' DRR measures vs. ‘hard’ DRR measures, by simply comparing the direct damages avoided such as crop loss, human injury and the deaths avoided based on the knowledge of past disaster events.,,,,,,Furthermore, interactive methods such as participatory ‘serious’ gaming may be used to address existing barriers and uncertainty. Instead of reducing DRR benefits and costs into a single metric such as B/C ratio and NPV, this type of participatory analysis takes the advantage of its complexity and uncertainty – by turning them into a fun and creative virtual space where community members and practitioners together explore potential solutions for DRR. These system-thinking based tools can be used to identify barriers to action such as cognitive and behavioral stumbling blocks  or institutional and political barriers that may challenge the implementation of DRRdespite our existing knowledge that DRR saves in the longer run, and make adjustments to our strategies accordingly. Second, for such tools to be useful beyond awareness raising, further efforts are certainly needed to systematically develop capacities and to collect locally applicable data in developing countries. Emerging initiatives such as crowd-and-expert-sourced hazard, exposure and vulnerability for example, offers potential avenues to collect risk information in data scarce environment.Looking beyond 2015, the demand for risk-based decision-making will likely increase. While best scientific knowledge should inform policy and practice in principle, it should not create an unrealistic expectation that the state-of-the art methods must be used in all cases. If decision-making tools, such as probabilistic CBAs, are to be useful (rather than be constraining), there are number of areas where further research and capacity building are required. First and foremost, the use of quantitative risk appraisal tools at community levels should be viewed as a vehicle for engagement and learning. We must critically reflect on why we continue to under-invest The authors have declared that no competing interests exist.


The 52nd Directing Council of the Pan American Health Organization (PAHO), in response to a call for action of the Minister of Health of El Salvador, recognized chronic kidney disease from nontraditional causes (CKDnT) affecting agricultural communities in Central America as a serious public health problem that requires urgent, effective, and concerted multisectoral action http://www.paho.org/hq/index.php?option=com_content&view=article&id=9402). CKD-N18 data also show disproportionate mortality from the disease in males compared to females . However, many reports  females . Mortali females , which iCKDnT has been largely reported in some clustered farming communities traditionally burdened by socioeconomic disadvantages from northern Nicaragua Studies reveal that patients affected by CKDnT show a clinical and pathologic pattern of a tubule-interstitial disease CKDnT is a chronic and multifactorial condition that has been neglected for quite some time. The causes of this epidemic have not been elucidated yet. Several potential etiological factors have been considered The misuse of pesticides has been widespread in Central America for a long time Harsh working conditions, especially regular exposure to very hot temperatures and extreme physical effort, lead to heat stress and dehydration. Along with exposure to pesticides, these seem to play an important role in the occurrence of the disease, particularly among sugarcane cutters Many questions related to these potential causative agents remain unanswered. For example, why is there such an important difference in the distribution of CKD between countries? Are there differences in the agricultural practices and work processes in areas with the same climatic characteristics and devoted to the same type of plantations ? Which types of agrochemicals have been used in the affected areas? How do we explain cases in nonsugarcane cutters, as well as in women?Other hypothesized causal agents merit further investigation. Nonsteroidal anti-inflammatory drugs, alcohol, and sugary beverage consumption have been associated with the disease A CKDnT regional research agenda is imperative not only to drive efforts to determine the epidemic's causative agents but also to bridge the gap between research and public health interventions. However, much-needed research must not delay action to address CKDnT. The resolution on CKDnT in Central America approved by PAHO's Directing Council The resolution of PAHO


Maintenance of genetic variance in secondary sexual traits, including bizarre ornaments and elaborated courtship displays, is a central problem of sexual selection theory. Despite theoretical arguments predicting that strong sexual selection leads to a depletion of additive genetic variance, traits associated with mating success show relatively high heritability. Here we argue that because of trade-offs associated with the production of costly epigamic traits, sexual selection is likely to lead to an increase, rather than a depletion, of genetic variance in those traits. Such trade-offs can also be expected to contribute to the maintenance of genetic variation in ecologically relevant traits with important implications for evolutionary processes, e.g. adaptation to novel environments or ecological speciation. However, if trade-offs are an important source of genetic variation in sexual traits, the magnitude of genetic variation may have little relevance for the possible genetic benefits of mate choice. Darwin  developeMaintenance of genetic variation in sexually selected traits has attracted much attention from evolutionary biologists, since prominent hypotheses for the evolution of sexual preferences assume genetic benefits for choosy females. Such indirect benefits of mate choice can stem either from positive feedback arising because the choosy sex  will produce progeny inheriting not only sexual attractiveness but also genes for preferences Fisher , or becaA) in trait combinations associated with the direction of selection, even though there is ample VA in individual traits  is presumably usually lower than that of life-history traits, they are nevertheless costly to produce. Thus the elaboration of a sexual trait should depend on the resources available to an individual. Based on this, the “genic capture” hypothesis posits that genetic variation in the expression of sexual traits represents genetic variation in resource acquisition and utilisation efficiency, or “condition”  play in maintaining genetic variation either via balancing selection, or by affecting mutation-selection balance  in horn size. Horned males have higher reproductive success, but lower survival , resulting from sexually dimorphic effects of alleles on female and male phenotypes  in weaker selection against deleterious mutations. Consequently, sexually-antagonistic mutations are expected to segregate in populations for longer than mutations deleterious for both sexes, resulting in larger amounts of genetic variance segregating in populations  unlock a number of ways by which genetic variance can be maintained. In the next two sections we consider the consequences of the nature of that variation for sexual and natural selection.One of the leading hypotheses proposed to resolve the lek paradox is the genic capture mechanism . If benefits to females of mating with the most competitive males were assumed to be large, extreme values of male traits evolve. In case of small benefits, arguably a more likely situation in case of genetic benefits of mate choice, trade-offs caused cyclical dynamics of sexually selected traits, such that their elaboration can decrease at some points of the cycle, followed by directional selection leading again to extreme trait elaboration. Under this scenario, preferences for epigamic traits easily evolve and are maintained in populations  and species turnover rate  is likely to impose antagonistic selection on many genes involved in basic organismal processes. Consequently, in as much as such trade-offs contribute to the maintenance of genetic variation (Connallon and Clark Conversely, fluctuations in ecological conditions can have consequences for the evolution of sexually selected traits and mate choice that are also worth exploring more fully. In our opinion, the realisation of the consequences of sexual selection for the maintenance of genetic variance in sexually selected traits opens new research perspectives in several areas of evolutionary biology.