An important assumption underlying meaningful comparisons of scores in rater-mediated assessments is that measurement is commensurate across raters. When raters differentially apply the standards established by an instrument, scores from different raters are on fundamentally different scales and no longer preserve a common meaning and basis for comparison. In this study, we developed a method to accommodate measurement noninvariance across raters when measurements are cross-classified within two distinct hierarchical units. We conceptualized random item effects cross-classified graded response models and used random discrimination and threshold effects to test, calibrate, and account for measurement noninvariance among raters. By leveraging empirical estimates of rater-specific deviations in the discrimination and threshold parameters, the proposed method allows us to identify noninvariant items and empirically estimate and directly adjust for this noninvariance within a cross-classified framework. Within the context of teaching evaluations, the results of a case study suggested substantial noninvariance across raters and that establishing an approximately invariant scale through random item effects improves model fit and predictive validity. The use of rater inferential judgment is a common and persistent feature of assessments designed to measure latent constructs across many different fields of research  cross-classified among other distinct hierarchical units . To do so, we extend cross-classified (multilevel) graded response models to incorporate random item (discrimination and threshold) effects to test, calibrate, and account for measurement noninvariance among raters. By leveraging empirical estimates of rater-specific deviations in the item parameters, the proposed method affords identification of noninvariant items and empirical estimation and direct adjustment for noninvariance within a multilevel or cross-classified framework.To explore the value of the approach, we applied the proposed method to a case study of repeated classroom measures of teaching quality using three primary questions. First, we investigated the extent to which there was evidence of measurement noninvariance among raters in cross-classified rater-mediated assessments of teaching. Second, we examined the extent to which allowing item parameters to vary across raters improved the relative and absolute fit of the measurement model as compared to models that assume invariant item parameters. Finally, because a primary criterion for the validity of classroom observations is their efficacy in predicting student achievement gains, we assessed the extent to which allowing item parameters to vary across raters improved the predictive efficacy of observation scores as compared to more conventional approaches.Raters have played a critical role in evaluating a wide range of psychological, cognitive, and physical traits. For example, teachers have been used as raters to assess students' medication use and deviant behavior Conners, ; teacherThe impetus for the use of rater-mediated assessments stems largely from the position that they often allow for more authentic and relevant assessments, thereby improving support for the validity of an assessment. Despite the flexibility and authenticity offered by rater-mediated assessments, they are often paired with features that, without proper treatment, can undermine their validity and reliability. In particular, a key threat to their validity is the construct-irrelevant variance introduced by the differences among raters in how they award scores Messick, .Research across multiple disciplines has demonstrated that such differences manifest in a number of common ways. Perhaps the most commonly cited rater effect is the differences among raters in terms of the severity with which they apply their evaluations. Differences in severity occur when some raters provide ratings that are consistently more severe relative to other raters , assessments are often obtained through the judgmental scoring of participants on targeted indicators  by individual judges. The structure of this design is often considered to have a multilevel organization because participants are hierarchically nested within raters. As previously noted, an important implication of this design is that, to the extent that raters vary in their application of the instrument standards, participants judged by the same rater share construct-irrelevant variation owing to differences among raters. As a result, the nested structure of this design potentially confounds variation in the underlying construct with differences among raters because variation in awarded scores incorporates variation owing to both of these components.i in for participant t rated by rater r as following a multilevel IRM .Because the goal of rater-mediated assessments is to assess participants free of rater influence, research has accounted for rater differences by introducing rater effects through, for example, a multilevel item response theory framework .Here, the probability of obtaining a one on an item is specified as a function of the level of the targeted construct for participant Separate from the nesting of participants in raters, rater-mediated assessments frequently introduce, or sustain other design features that further contribute to construct-irrelevant variance. For instance, repeated measures designs are often purposefully employed in conditions where measurement is known to be unreliable or sensitive to context . Because such excess variance is specific to an observation and rater and does not generalize beyond a sampled observation and rater, research has accounted for these effects by introducing observation- and rater-specific random effects  observation-specific deviations for observation o in participant t (αot).Equation (2) follows the aforementioned notation but now expands to accommodate (a) repeated measurements such that To assess and substantiate invariance in these applications or correct for noninvariance, there have been three typical approaches: full, partial, and approximate invariance. Below we briefly outline their structure, application, and limitations as they may apply to rater-mediated assessments.The conventional approach to assessing/establishing invariance across subgroups is through multiple group analyses. For instance, continuing with the aforementioned notation from the repeated measures cross-classified model (2), full invariance across raters supports no longer holds]. When there is evidence of measurement noninvariance, a common alternative approach is to adjust for noninvariant items using a partial measurement invariance approach  solely address latent trait variation across facets because they (only) decompose the variation in a latent trait into components uniquely attributable to each facet and do not address how item parameters vary across facets. Put differently, the latent trait side random effects models presented above account for the extent to which the latent trait of a participant is deflected by, for example, the relative severity of a rater and/or the atypical nature of an observation. In this way, latent trait side random effects models accommodate threshold differences among raters and observations only if these differences manifest consistently and uniformly for all items. If rather threshold differences among raters/observations vary across items or if discrimination parameters differ, latent trait side random effects models will not be sufficient to separate the latent trait from item characteristics because measurement is not invariant across facets.Rather, in the presence of item side variance, separation of the latent trait from item characteristics would require direct treatment of measurement noninvariance. Applied to cross-classified rater-mediated assessments, conventional approaches, such as the partial invariance approach, are however particularly challenging because studies tend to draw on large number of raters and only a small number of items per latent trait. To relax assumptions of measurement invariance across raters, we developed a random item effects cross-classified (multilevel) graded response model. Our specification first drew on a graded response model parameterization such that observed item scores were treated as fallible ordinal ratings stemming from a targeted latent trait. Second, because many rater-mediated assessments operate within cross-classified (multilevel) designs, we leveraged a cross-classified (multilevel) graded response model to introduce random effects for distinct hierarchical units . Third, we accommodated noninvariance across raters by permitting item discrimination and threshold parameters to vary across raters  using random item effects Fox, . Under aYiotr is the ordinal score for item i in observation o for participant t rated by rater ir, a represents the average discrimination parameter for item i across all raters, θt represents a participant's persistent level of the targeted latent trait , ira is item i's discrimination parameter under rater r, otα is the latent trait deviation specific to observation o for participant t, and rγ is the deviation capturing consistent differences among raters in terms of their relative severity across all items. Let K represent the number of categories items are graded on with k as a specific category and let d(1)ir, …, dK − 1), α ~ N, γ ~ N, air ~ N, and dkir ~ N.Here In this particular specification, we used an independent random item effects structure and restricted item parameters to vary across only a single level two unit (raters). However, the model could be further extended to consider covariance among random item effects parameters and/or to allow item parameters to vary across both level two units . Similarly, we applied the mean item parameters across raters as the inter-rater item parameters and use these to construct an inter-rater scale. However, there are many reasonable and potentially more appropriate alternatives.t) separate from the observation level discrimination parameter (ira).For instance, one alternative specification estimates the discrimination parameter applied to a participant's persistent level of the targeted latent trait (θao)(ir as the observation level discrimination parameters (where ao)(ir ~ N(ao)) and introduce at).Here we now use The proposed model can also be adapted to accommodate other cross-classified or multilevel structures. For example, as noted earlier, many measurement designs operate within larger multilevel structures. Consider for example a design in which participants are cross-classified among raters and schools in which we track measurement noninvariance across raters. Under this design, the targeted latent trait of a participant now operates at lowest level of the hierarchy. With some slight changes in notation we can modify Equation (4) so thatYitsr is the ordinal score for item i of participant t in school s rated by rater ir, a represents the average discrimination parameter for item i across all raters, θs represents the school effect or school-specific deviation in the latent trait, ira is item i's discrimination parameter under rater r, αts is participant t's level of the targeted latent trait, and γr is the deviation specific to rater severity. Remaining notation and constraints are unchanged.Here Our formulation of approximate measurement invariance models for rater-mediated assessments within a cross-classified (multilevel) structure is an extension of the multilevel IRM with random item effects Fox, . The proAs noted earlier, construct-irrelevant variation can be conceptually split into two principal sources—latent trait and item side variation. Latent trait random effects  serve to decompose the variation in a latent trait across facets. In contrast, item side random effects serve to capture the extent to which items function differently across hierarchical units. By simultaneously introducing latent trait and item side random effects, we permit a latent trait to vary across hierarchical units and items to function differently across those hierarchical units. When the proposed model fits the data, decomposing the latent trait and adjusting for differential item functioning across raters through random effects can establish an inter-rater scale such that the latent trait is separable from construct-irrelevant variation. In this way, estimates of a targeted latent trait from models that accommodate both latent trait and item side variation are more likely to generalize beyond the sampled observations and raters.The key addition in the approach is the introduction of item side random effects across raters within a cross-classified framework. Random item effects are intended to not only identify noninvariance but also to track it through empirical estimates of the differences among raters. Under a Bayes approach, empirical estimates of rater-specific differences in item parameters are obtained using a mix of the inter-rater item parameters, which are based on all observations, and rater-specific item parameters, which are based on the particular observations a rater has rated. Rater-specific differences in item parameters are estimated using a shrinkage estimator where the amount of shrinkage toward the inter-rater estimates is a function of how precisely we can identify raters' differences from the mean. In this way, random item effects allow us to borrow strength from the larger pool of raters to improve estimates for individual raters, especially those for which we have little information. The shrinkage of rater-specific item parameters toward inter-rater parameters has been shown to reduce the mean-squared error of rater-specific estimates and is widely used elsewhere  among more conventional models, a single level IRM assumes that associations among items derive solely from a targeted latent trait. A multilevel IRM with observations nested within participants (ignoring raters) suggests that associations among items derive from a persistent component of a targeted latent trait and observation-specific deviations. Use of a cross-classified IRM with observations cross-classified among raters and participants suggests associations among items are a function of a persistent component of a targeted latent trait, observation-specific deviations, and deflections due to consistent differences in severity among raters. In these latent trait side (only) random effects models, item parameters are assumed to remain equal across raters. If we further introduce random item effects into the cross-classified model (Equation 4), we relax this assumption of equality of item parameters across raters and allow the discrimination and threshold parameters to vary.iotrZ. Under this formulation, an observed ordinal response, Yiotr, is used as an item of a normally distributed latent item response, iotrZ, which is placed into a response category defined by threshold parameters dkir such that iotrZ is defined asThe cross-classified structure of this model combined with the potential for a large number of latent variables renders maximum likelihood estimation computationally challenging with even a few items because it would require high dimensional numerical integration. A more practical option in this context is Bayesian methods . That is, if the variance of the random item effects is zero, item parameters are consistent across raters and measurement is invariant. However, departures from zero for specific items suggest that measurement is noninvariant across raters because the relationship between an item and the latent trait is not consistent across raters.Having introduced random item effects to accommodate measurement noninvariance across raters, a relevant question is how we might test for evidence of (non)invariance. If measurement invariance holds, the variance of the random item effects across raters should be zero  evidence of noninvariance, (b) improvements in relative and absolute fit, and (c) improved predictive validity. Although we use this application as an initial case study of the proposed method, we are cautious to note that the correct underlying model is unknown because it is an empirical investigation. For this reason, the extent to which differences among approaches represent true gains or the extent to which these gains might be generalizable is unknown and needs to be studied further.In assessments of teaching quality, classroom observations of teaching are generally carried out by having trained raters evaluate teachers across multiple observations using a fixed set of items. Teaching evaluation instruments typically focus raters' attention on behaviors that exemplify an implicit theory of effective teaching. For each item, the guiding rubric that accompanies each instrument typically provides specific examples and descriptive anchors for each category of a scale and raters typically provide ordinal assessments for each item in each observation.Like other types of rater-mediated assessments, a significant source of construct-irrelevant variation in classroom observations is differences among raters in their judgments  classroom observation system  and then passed a subsequent certification exam. Raters also completed weekly calibration exercises where their scores were compared to master scores on clips of instruction. These scores were discussed in weekly webinars with master raters to help prevent rater drift. Raters who demonstrated problematic scores or rationales were remediated by master raters.To measure student achievement, we used a researcher developed test administered to students in all four districts during the fall and spring semesters of the 2010–11 and 2011–12 school years. Items on this low-stakes mathematics assessment were designed to align with fourth and fifth grade Common Core mathematics standards, and covered topics such as numbers and operations, algebra, and geometry and measurement. Reliability of the test ranged from 0.82 to 0.89, depending on the form ; and residual effects for the teacher (μt), time, and student . To estimate the underlying teacher effect or “value-added” score, we used the empirical Bayes residual for each teacher.The outcome variable, We applied the previously described random item effects cross-classified graded response model (Equation 4). We estimated the models in Mplus using the default diffuse prior distributions (see Appendix). Prior distributions for the discrimination parameters were normal with mean zero and variance five; for the thresholds the prior distributions were normal with mean zero and infinite variance, and for the variance parameters the prior distributions were log uniform bounded by negative and positive infinity. Subsequent inferences were conducted on the posterior medians and standard deviations. For each model, we ran two chains using a burn-in of 25,000 MCMC iterations and up to 100,000 post-burn-in iterations with convergence determined by the default potential scale reduction criteria implemented in Mplus and Gelman-Rubin diagnostics  prior with a shape parameter value of one and a scale parameter value of 0.005. We then explored the absolute fit using simple posterior predictive checks  for the variance of each item parameter to test the null hypotheses that each of the variances was less than 0.001, 0.01, or 0.1. Using a common cutoff of about three for Bayes factor, the results for each threshold and discrimination parameter uniformly indicated that the variance of the random effects was different than zero , decreased the correlation by about 10%. However, once we allowed for random item effects, the cross-classified model again increased the correspondence between observation and value-added scores. Moreover, although 95% intervals for the correlation between observation and value-added scores included zero across models without random item effects, the 95% interval for the correlation excluded zero for the model with random item effects.Although strict measurement invariance across raters is optimal, the reality is that it will rarely hold in rater-mediated assessments. Developing measurement models that are more tightly attuned to the types of measurement errors present in rater-mediated assessments is likely to improve the validity and comparability of scores across raters and other sources of construct-irrelevant variation. The proposed method relaxes assumptions of measurement invariance in cross-classified (multilevel) rater-mediated assessments by introducing random item effects to test for noninvariance and empirically construct an inter-rater scale. More conceptually, the approach helps to identify the “ruler” each rater uses to conduct his/her assessments, construct an inter-rater scale, and make adjustments to observed scores in order to place them on this inter-rater scale.Evidence from the case study on teaching quality suggested the promise of random item effect models in addressing noninvariance in rater-mediated assessments. The results indicated that measurement was noninvariant across raters for each item and suggested that direct adjustments for this noninvariance through random item effects improved model fit and the predictive validity of the teaching quality. These results are consistent with prior literature in that they suggest that ignoring measurement noninvariance can obscure both the psychometric properties of a scale and the underlying relationships among variables.As noted previously, the results presented in this study are only based on a single case study and do not necessarily imply these findings will generalize. However, although the authority of the proposed model over alternative models is unclear in our empirical application, the more flexible assumptions of the proposed model with regard to measurement noninvariance would seem to lend greater credence to its results. Nevertheless, the circumstances under which the proposed method outperforms alternative methods need to be systematically studied in greater detail to understand the extent to which findings are robust to key assumptions.In this regard, we highlight four areas that warrant further study. First, the flexibility of the proposed framework suggests many different alternative forms and we have presented just a few limited forms. For instance, we chose to define inter-rater parameters as the average of item parameters and apply those values to the teacher level construct. However, there are many reasonable alternatives including not linking parameters at hierarchical levels to those at the lower level at all and independently estimating them. Future research will need to investigate alternatives, develop tests for comparing the fits of non-nested models, and examine the extent to which results are robust to these choices.post-hoc analyses examining the tenability of the normality assumption for each item parameter using the Shapiro–Wilks test of normality were conducted. Each test suggested that we could not reject the null hypothesis that the random item effects came from a normal distribution. However, this assumption may be untenable if, for example, items are invariant across most raters but demonstrate substantial invariance for a handful of raters. In this case fixed multiple group approaches are potentially more appropriate. Similarly, its reasonable to suspect that random item effects may not be independent. In post-hoc analyses we re-estimated the proposed model using a multivariate normal distribution for the random item effects. Our results indicated virtually no correlation among the random effects. However, for many assessments, its reasonable to suspect that a rater who is above average at discriminating on one item may also be above average at discriminating on other items.Second, in our application we assumed random item effects were independently normally distributed. For our case study, Third, having established noninvariance, an important follow-up question examines the extent to which rater characteristics systematically predict noninvariance. For example, do raters with more years of experience demonstrate a greater capacity to discriminate among quality levels? To address this line of inquiries, the proposed model can be further extended to include explanatory components such that random item effects are modeled as a function of fixed rater characteristics through a latent regression framework  but omitted the overall adjustment for rater severity (γr). Our results indicated that absolute fit remained the same but that the correlation between observation and value-added scores increased to 0.20. Again, although the authority of these differences is unknown, these results question the conventional wisdom of including broad sweeping and uniform adjustments for rater severity. Future investigations should examine the fidelity of such adjustments and further consider the efficacy of interactions among the facets. For instance, literature has found that raters function differently across subgroups so that they are more severe within certain subgroups than others.Fourth, the results of our case study suggested that adjustment for persistent differences in severity among raters actually decreased the correspondence between observation and value-added scores. More specifically, when we compared the results of the multilevel model that did not adjust for rater effects at all with that of the cross-classified model with rater severity adjustments (but no random item effects), the correlation between teaching and value-added scores decreased (see Multilevel vs. CC in Table In conclusion, meaningful comparisons among participants on latent traits in rater-mediated assessments require measurement to be invariant across raters. In many instances, this assumption will be unrealistic. The proposed method offers a flexible alternative that can accommodate measurement noninvariance within multilevel and cross-classified frameworks even when there are no invariant items. Our results suggest the approach is promising and flexible but that it needs more investigation.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.


Sex chromosomes can evolve once recombination is halted between a homologous pair of chromosomes. Owing to detailed studies using key model systems, we have a nuanced understanding and a rich review literature of what happens to sex chromosomes once recombination is arrested. However, three broad questions remain unanswered. First, why do sex chromosomes stop recombining in the first place? Second, how is recombination halted? Finally, why does the spread of recombination suppression, and therefore the rate of sex chromosome divergence, vary so substantially across clades? In this review, we consider each of these three questions in turn to address fundamental questions in the field, summarize our current understanding, and highlight important areas for future work. Sex chromosome evolution begins when recombination between a homologous pair of chromosomes is halted. Here, Wright et al. review our current understanding of the causes and mechanisms of recombination suppression between incipient sex chromosomes and suggest future directions for the field. Sex chromosomes have evolved independently many times throughout the eukaryotes, and represent a remarkable case of genomic convergence, as unrelated sex chromosomes share many properties across distant taxa124Drosophila679101471121312Owing to detailed studies in Amhr2 locus appears to control sex in the tiger pufferfish (Takifugu rupripes)18Why recombination is suppressed in the first place is less clear, as the chromosomes that determine sex in many organisms with genetic sex determination never progress to heteromorphic sex chromosomes. For example, a single missense single nucleotide polymorphism in the coding region of the These observations indicate that recombination suppression and sex chromosome divergence are not inevitable consequences of genetic sex determination, leading to three questions at the heart of sex chromosomes evolution. First, why do sex chromosomes stop recombining? Second, how is recombination suppression achieved? Third, why does the spread of recombination suppression, and therefore the rate of sex chromosome divergence, vary so substantially across clades?per se. Recombination rate has long been known to be a critical factor in the ability of a genomic region to respond to selection. Dobzhansky and colleagues222324262728The implications of these questions go far beyond sex chromosome research Poecilia reticulataThe most commonly accepted theory of sex chromosome evolution1431Although the sexual conflict model of sex chromosome evolution remains widely accepted, the evidence for or against it is remarkably slim. Non-adaptive alternatives have been suggested as well34Drosophila37DrosophilaImportantly, it can be difficult in ancient systems to differentiate cause from consequence. For example, the gene content of the Y chromosome has been interpreted as supporting the role of sexual conflict in sex chromosome evolution. The Y chromosome in mammalsAnolis lizards422144484950Gasterosteus aculeatus), where a neo-sex chromosome fusion in the Sea of Japan population may have been driven, at least in part, by sexual conflictEvidence from sex chromosome systems at earlier stages of divergence is therefore key to understanding why sex chromosomes evolve, and there are a wealth of systems with early stage sex chromosomes including The theory of sex chromosome evolution articulated above assumes that the separation of the sexes, called gonochorism in animals and dioecy in plants, predates the evolution of sex chromosomes. Because of this assumption, the theory is in many ways more applicable to animals, which are more often gonochoristic. Dioecy is rare in plants, which restricts the evolution of sex chromosomes to fewer taxa. In flowering plants (angiosperms), only 5–6% of all species have separate male and female genders56In plants and other systems where sex chromosomes are associated with transitions from hermaphroditism to separate sexes, sex chromosome formation may take a slightly different route than in species with ancestral separate sexes. In this case, the dominant model49Regardless of why sex chromosomes originate, the process of sex chromosome evolution necessitates halting recombination between the nascent X and Y in males, or Z and W in females. Therefore, sex chromosome evolution at the most basic level requires sex-specific recombination patterns on the sex chromosomes. Recombination varies substantially in males and females, both in frequency and in specific hotspots, referred to as heterochiasmy. An extreme example of this is achiasmy, where recombination only occurs in one sexAchiasmy may either precede or follow emergence of a nascent sex determining locus62In species where both sexes recombine, some mechanism is needed to block recombination between the sex determining gene and nearby genes with sex-specific effects in the heterogametic sex. Chromosomal inversions spanning the sex determining locus and nearby sexually antagonistic loci are often assumed to halt recombination and therefore to drive sex chromosome divergence10204866675369Recombination is dynamic and heterogeneous, and the rate of recombination varies extensively throughout the genome and between the sexes63Recent work on recombination evolution has suggested that sequence characteristics, namely binding motifs and structural traits, can exhibit short-term evolutionary dynamics that can lead to rapid shifts in local recombination rates73747673787174Many organisms with genetic sex determination lack heteromorphic sex chromosomes, indicating that the non-recombining region has not spread significantly beyond the sex determining locus. Examples of animal systems with homomorphic sex chromosomes include the pufferfish18First, some homomorphic sex chromosomes are young and may be in the early stages of degeneration, for example in papaya49Some organisms have a long haploid phase, resulting in strong haploid purifying selection acting to maintain gene activity on the Y chromosome7083After recombination has been halted between the sex chromosomes, the non-recombining Y or W chromosome decaysDrosophila and the X-added region of the eutherians. In both these cases, an existing system of complete dosage compensation quickly spread onto the expanded X chromosome90Much of our understanding of Y chromosome decay comes from the neo-sex chromosomes in Drosophila and eutherian Y, and it was recently suggested that this difference is largely due to the opposing effects of male-biased mutation on Y and W chromosomes1Drosophila neo-sex chromosomes and the eutherian X-added region, as well as suggesting that the dichotomy between Drosophila and eutherians versus birds might not be heterogamety (XY versus ZW), but rather complete versus incomplete dosage compensation. Recent work in sticklebacks, a male heterogametic system with incomplete dosage compensation, indicates that purifying selection remains strong on dosage sensitive Y genesThe slow rate of gene decay recently observed on the W chromosome in birdsSex reversal, discordance between an individual's phenotypic and genotypic sex, may be important in recombination suppression and sex chromosome evolution. In many ectotherm vertebrates, such as amphibians952199Sexually antagonistic alleles are central to the sexual conflict model of sex chromosome evolution102Three major questions regarding the evolution of sex chromosomes remain unanswered. To answer them, it will be important to move well beyond the main model systems, and develop new study systems at earlier stages of sex chromosome divergence.Does sexual conflict drive sex chromosome evolution? The role of sexual conflict in driving sex chromosome evolution, although widely accepted, remains fundamentally unknown, largely due to difficulties in identifying sexually antagonistic alleles directly. In order to answer this question, it is important that we develop new study systems with far younger sex chromosomes. Crucially, these study systems will also need to have some phenotypic trait or traits that are known to be sexually antagonistic, with known underlying genetic architecture. Alternatively, experimental evolution of sexual conflict may prove useful in studying changes in sex-specific recombination rates.How is recombination suppressed between the sex chromosomes? The mechanisms underlying recombination suppression are still largely unknown. Inversions are often assumed to facilitate sex chromosome divergence through recombination suppression, but this assumption is contradicted by the heterogeneity in divergence observed in young sex chromosome systems. Moreover, in old sex chromosome systems, it may be impossible to determine whether inversions catalyze sex chromosome evolution or are a consequence of recombination suppression achieved through other means. This difficulty in differentiating cause and effect again suggests that study systems with nascent sex chromosomes are crucial for understanding the cause of recombination suppression.Why do rates of sex chromosome divergence vary so significantly across groups? Preliminary evidence suggests that the presence or absence of complete dosage compensation, the relative length of the haploid phase in the life cycle, and the prevalence and fertility of sex reversed individuals might be the largest predictors of the power of purifying selection to maintain gene activity on the sex-limited chromosome, and therefore the rate of gene loss once recombination is halted. The pervasiveness of sexual conflict throughout the genome may also be important. Untangling the role of these different characteristics in explaining the rate of sex chromosome divergence will require very large-scale comparative datasets and phylogenetic methods. Work in this direction has startedHow to cite this article: Wright, A.E. et al. How to make a sex chromosome. Nat. Commun. 7:12087 doi: 10.1038/ncomms12087 (2016).


In patients with left ventricular non-compaction (LVNC), implantation of a left ventricular assist device (LVAD) may be performed as a bridge to transplantation. In this respect, the particular characteristics of the left ventricular myocardium may represent a challenge.We report a patient with LVNC who required urgent heart transplantation for inflow cannula obstruction nine months after receiving a LVAD. LVAD parameters, echocardiography and examination of the explanted heart suggested changes of left ventricular configuration brought about by LVAD support as the most likely cause of inflow cannula obstruction.We conclude that changes experienced by non-compacted myocardium during LVAD support may give rise to inflow cannula obstruction and flow reduction. Presence of LVNC mandates tight surveillance for changes in LV configuration and LVAD flow characteristics and may justify urgent transplantation listing status. Left ventricular non-compaction (LVNC) is attributed to arrest of normal embryogenesis of the endocardium and myocardium and results in a two-layered structure of the left ventricle (LV). In addition to a compacted outer layer, the LV comprises a spongy non-compacted inner layer with heavy trabeculation and deep intertrabecular recesses , 2. ThouWhile previous authors focused on thromboembolic events , 7 and aA 35-year-old male with LVNC underwent off-pump LVAD implantation  through a minimally invasive access. Presence of trabeculation obstructing the inflow cannula was excluded by digital exploration before introduction of the LVAD. Correct inflow cannula position and absence of obstruction were additionally verified by transesophageal echocardiography and evaluation of LVAD flow behaviour before closure. After an uneventful hospital stay and subsequent exercise tolerance and quality of life improvement, the patient presented with low flow alarms and had his LVAD speed re-adjusted several times. After nine months, he was readmitted for perilously low flows that intermittently dropped to 500 ml/min. This was interpreted as the consequence of an excess of outdoor activity and volume depletion, and when LVAD flows increased satisfactorily after administration of fluids, the patient was discharged the next day. Subsequently, LVAD flows kept dropping intermittently over a few weeks, and finally the patient ceased to respond to administration of fluids and developed signs of heart failure. He was re-admitted, and his waiting list status was set to high urgency.After four weeks of medical treatment, he was put on extracorporeal life support (ECLS). By that time, changes in LV configuration had come to be suspected as the cause of LVAD dysfunction. Echocardiography showed the LV cavity smaller and the LV walls thicker than before LVAD implantation, with heavy trabeculation within the LV and a solid structure appearing to cross in front of the inflow cannula opening Fig. .Fig. 1TrAfter 45 days on ECLS, the patient underwent heart transplantation. Macroscopic examination of the explanted heart confirmed the findings on echocardiography. The LV cavity was narrow and partially obliterated by dense tissue. In particular, there was a rigid trabecular structure stretching across the LV in front of and appearing to have overgrown the LVAD inflow cannula. The left ventricular wall showed massive thickening to nearly 30 mm, with the myocardium spongy and interspersed with yellowish fatty deposits Fig. .Fig. 2HeLVNC was found to lead to severe heart failure in a considerable share of those diagnosed with the condition, with 47 %  and 60 %Ninios et al.  reportedThe latter finding is in keeping with previous literature reporting the typical features of LVNC to be located predominantly in the apical and mid-ventricular segments of the LV , which iIn our case, off-pump HVAD implantation was uncomplicated, obstruction of the inflow cannula by apical trabecular structures was excluded by digital palpation as well as by transesophageal echocardiography, and unhindered blood flow into the inflow cannula was reflected by normal LVAD flow characteristics. In hindsight, however, on-pump implantation would have allowed not only inspection of the left ventricular apex, but also excision of excess tissue. On the other hand, the fact that first signs of inflow cannula obstruction occurred after several months of uneventful support and absence, in earlier echocardiographic examinations, of the heavy apical and mid-ventricular trabecular masses seen on echocardiography after readmission for LVAD dysfunction suggest that at least part of the changes that finally resulted in inflow cannula obstruction must have occurred over time.While decompression of the LV is a normal and desirable consequence of LV unloading, the extreme degree of narrowing of the LV cavity we saw in the explanted heart as well as the heavy mass of rigid trabeculated tissue around the inflow cannula represent unusual findings. They are most likely explained by LV configuration and the geometry and density of pre-existing trabeculated tissue having changed in response to the hemodynamic changes that were brought about by LVAD support.We conclude that LVNC may turn out to be a cause of inflow cannula obstruction and flow reduction even where LVAD function was normal upon implantation. On-pump implantation may be advisable with a view to inspecting the inflow opening and excising excess tissue, thus preventing subsequent catastrophic inflow obstruction. LVNC requires a high index of suspicion and mandates tight surveillance of LVAD flow characteristics and LV configuration. If LVNC actually turns out to be a limiting factor in LVAD therapy, it may justify more liberal access to high urgency listing for patients afflicted with this particular condition.ECLS, extracorporeal life support; HVAD, left ventricular assist device supplied by HeartWare Inc; LV, left ventricle, left ventricular; LVAD, left ventricular assist device; LVNC, left ventricular non compaction; VAD, ventricular assist device


Ankle osteoarthritis (AOA) is a severe pathology, mostly affecting a post-traumatic young population. Arthroscopic debridement, arthrodiastasis, osteotomy are the current joint sparing procedures, but, in the available studies, controversial results were achieved, with better outcomes in case of limited degeneration. Only osteotomy in case of malalignment is universally accepted as a joint sparing procedure in case of partial AOA. Recently, the biological mechanism of osteoarthritis has been intensively studied: it is a whole joint pathology, affecting cartilage, bone and synovial membrane. In particular, the first stage is characterized by a reversible catabolic activity with a state of chondropenia. Thus, biological procedures for early AOA were proposed in order to delay or to avoid end stage procedures. Mesenchymal stem cells (MSCs) may be a good solution to prevent or reverse degeneration, due to their immunomodulatory features (able to control the catabolic joint environment) and their regenerative osteochondral capabilities . In fact, MSCs may regulate the cytokine cascade and the metalloproteinases release, restoring the osteochondral tissue as well. After interesting reports of mesenchymal stem cells seeded on scaffold and applied to cartilage defects in non-degenerated joints, bone marrow derived cells transplantation appears to be a promising technique in order to control the degenerative pathway and restore the osteochondral defects. Ankle osteoarthritis (AOA) is a severe disabling pathology affecting 1 % of the adult population  at medium follow-up, after arthroscopic debridement , six out of 22 patients treated with ankle distraction failed, requiring arthrodesis or resulting in Sudeck athrophy  is characterized by an articular tissue and microenvironment alteration involving all joint components: beyond cartilage, subchondral bone and synovial membrane  make a cell based approach suitable for early AOA. MSCs are multipotent stromal cells that can differentiate in several cell types responding to local environmental stimuli such as cytokines and growth factors, which are released in response of tissue injury  and small molecules seem to be an answer since they are able to regulate multiple molecular pathways and cellular processes such as differentiation (Nöth et al. Treatment of early AOA is still debated and no clear guidelines are currently available. Joint sparing procedures are recommended in young patients with AOA, but the results are not so positive and sometimes contradicting: only osteotomy in case of malalignment is universally accepted. Recently, a great interest about biological procedures in early degenerative disease has aroused. Mesenchymal stem cells may play a crucial role in case of degeneration, due to their immunomodulatory peculiarities and the their regenerative prompt: the two features may allow a whole joint approach in case of AOA, regulating the cytokine cascade and restoring the osteochondral tissue as well. Few sporadic data are available about mesenchymal stem cells in degenerated joints, sometimes using an injective procedure and sometimes applying the cells on a scaffold, with encouraging results. In osteochondral defects, few reports about mesenchymal stem cells seeded on scaffold in non-degenerated joints are available: signs of osteochondral regeneration were described. It seems that the autologous bone marrow derived MSCs transplantation may be a promising procedure in order to modulate the degenerative pathway and restore the osteochondral defects.


Spontaneous  and synaThis study, employing the spatiotemporal mean-field Wilson-Cowan equations , provideUnderstanding the contrast between traveling and localized activity in synaptically-driven neural networks is an important task due to its wide range of applications to areas such as vision, sleep and epilepsy. Here, it was shown that a simple population model exhibits both modes of behavior. This result allows us to further study how various network properties such as density and connectivity strength give rise to these kinds of activity.


Effectiveness of alcohol policy interventions varies across times and places. The circumstances under which effective polices can be successfully transferred between contexts are typically unexplored with little attention given to developing reporting requirements that would facilitate systematic investigation.Using purposive sampling and expert elicitation methods, we identified context-related factors impacting on the effectiveness of population-level alcohol policies. We then drew on previous characterisations of alcohol policy contexts and methodological-reporting checklists to design a new checklist for reporting contextual information in evaluation studies.Six context factor domains were identified: (i) baseline alcohol consumption, norms and harm rates; (ii) baseline affordability and availability; (iii) social, microeconomic and demographic contexts; (iv) macroeconomic context; (v) market context; and (vi) wider policy, political and media context. The checklist specifies information, typically available in national or international reports, to be reported in each domain.The checklist can facilitate evidence synthesis by providing: (i) a mechanism for systematic and more consistent reporting of contextual data for meta-regression and realist evaluations; (ii) information for policy-makers on differences between their context and contexts of evaluations; and (iii) an evidence base for adjusting prospective policy simulation models to account for policy context.Our proposed checklist provides a tool for gaining better understanding of the influence of policy context on intervention effectiveness. Further work is required to rationalise and aggregate checklists across interventions types to make such checklists practical for use by journals and to improve reporting of important qualitative contextual data.  The effectiveness of alcohol policy interventions is rarely consistent across different times and places. Robin Room made a valuable contribution to how we think about heterogeneity in policy evaluation evidence when discussing unexpected null effects on alcohol consumption following alcohol affordability increases in the Nordic countries Concerns about the applicability of evidence to different contexts are partly driven by the increasing importance of ‘policy transfers’ over recent decades ceteris paribusRoom. argued that this interplay with policy context is often reduced to simple invocations of Despite the value of contextual data to successful policy transfer and evidence synthesis methods, there has been no established guidance for authors on reporting research context. Therefore, we propose the TRAICE checklist to address this gap. Recognising that a ‘one-size fits all’ checklist is not feasible due to the requisite information varying across interventions, we nevertheless believe some aggregation is possible. We thus designed TRAICE for reporting on evaluations of population-level alcohol policy interventions. We particularly focused on interventions restricting the availability or affordability of alcohol as this is where much of the population-level alcohol policy evidence lies The mechanisms by which population-level alcohol policies impact on alcohol consumption and related harms are well documented Room. have not provided a method for identifying context factors Our initial intention was to harness systematic review techniques and search publication databases  for studies that specifically consider the impact of one or more context factors on intervention effectiveness. Search strings included variants of the terms ‘alcohol*, liquor* and drink*’ combined with terms relating to ‘policy’ and ‘context*’, ‘setting’ or ‘environment*’. This initial scoping search revealed that the concept of context is typically absent from titles and abstracts although three articles using regression-based methods to quantify the effects on alcohol price elasticities of the following context factors were identified: time period, baseline consumption, retail licensing systems and population-level beverage preferences 22–24. As our systematic review approach was unsuccessful, we focused on two methods to identify context factors.Although few studies had specifically researched context factors, we noted many papers mentioned context in discussion sections when constructing explanations for study findings. Therefore, we analysed a purposive sample of 112 papers included in a recent review of alcohol price elasticities A further consideration was whether TRAICE should address all or only some of the identified context factors as this linked to issues of data accessibility, burden on authors and ability to standardise reporting. To develop TRAICE, the lead author produced an initial draft that sought to reconcile identified context factors with considerations of feasibility. This draft was then reviewed and revised by members of the research team in an iterative process analogous to that used when developing STROBE, CONSORT and PRISMA.The following step, decisions on the specific data to be recorded, was informed by documents with similar aims, such as the International Alcohol Control Study's ‘Alcohol Environment Protocol’ For the final design of the checklist, we sought to follow the format of established reporting checklists . These checklists seek to balance conciseness with detail. Each contains approximately 25 items to ensure reporting is comprehensive without imposing impractical burdens on authors. They prompt authors to identify where in their report (the page number) required information is provided. They mix required information with suggestions for further detail, if relevant. They also offer supporting information to aid checklist completion. We attempted to follow this structure while recognising that as TRAICE seeks to elicit a large amount of supplementary information to interpret findings, and this information may not be of interest to general readerships, some contextual detail may be best placed in appendices rather than integrated into the main report.The final list of context factors cover six broad contextual domains as detailed in Table At the centre of Figure Table aide memoire to good practice rather than a prescriptive document.In general, the checklist prioritises recording of quantitative data and places less weight on descriptions of less tangible factors . Although intangible factors are important, it is more challenging to standardise reporting for such factors. Instead, authors are encouraged to consider, and to provide additional information on, areas of specific relevance to interpretation of results (e.g. describing the tone and level of media debate or noteworthy industry responses to an intervention). Examples of ways these may be provided in quantitative form are given, although we acknowledge this may often not be possible. Authors are also encouraged to identify and describe relevant trends in key factors. For these aspects, TRAICE serves more as an Efforts to improve the use of scientific evidence in policy decision making rely in part on policy actors understanding the validity of evidence to their specific context. The proposed TRAICE checklist facilitates population-level alcohol policies by requiring that reports of evaluation studies provide research users with a more complete view of the context within which the evidence has been generated.The development process for TRAICE was strengthened by the use of multiple methods to identify context factors. The methods were similar to those used in other studies examining the contextual specificity of evidence One strength of TRAICE lies in it being relatively straightforward to complete for national-level evaluations with most information available in standard national statistical outputs or international reports. However, this simplicity is achieved by privileging measurable context factors over important but less tangible factors. As previously explained, this pragmatic decision sought to reduce burden on researchers and to facilitate standardisation. We welcome suggestions for how systematic reporting of less tangible contextual information may be achieved and encourage development of measures to facilitate this. It is desirable that reporting checklists minimise burden on researchers where possible and an obvious solution is to shorten the checklist. To do this requires an understanding of which items are most important and we welcome feedback and evidence in this area. TRAICE may be more difficult to complete for sub-national evaluations where data are less available and reporting national-level data may be a necessary compromise under such circumstances. An additional limitation is that TRAICE functions best when applied to evaluations conducted over short contemporary timeframes where the context is stable and data characterising it are readily available. For evaluations utilising long-term time series data covering a continually changing policy context, recording of contextual data may be more challenging and, again, we invite suggestions to facilitate a more nuanced use of contextual data.The TRAICE checklist can be used in three specific ways to further evidence-based policy-making. First, explicit and standardised recording of contextual data in future studies allows evidence synthesis techniques to exploit these data. For meta-analyses, each primary study would contain data on a set of variables potentially confounding estimates of policy effectiveness. These data could be easily extracted and entered into analytical software for use in meta-regressions with the independent effect of each context factor estimated within a meta-regression. Realist syntheses would also benefit as data would be readily available to allow the development and testing of hypotheses regarding impacts of context on policy effectiveness. Second, policy-makers assessing whether to undertake a policy transfer will have easier access to information on the salient differences between the research context and their own context. Although the policy process should not be mistaken for an exercise in scientific rationalism These potential gains are contingent on scientific journals adopting requirements for reporting of contextual data. Although TRAICE represents a step towards that goal, further work is required beyond resolving those methodological issues identified above. A key challenge is that TRAICE addresses only population-level alcohol policy interventions. Checklists for community-and individual-level interventions as well as interventions in other areas of public health are needed; however, journals cannot be expected to compile compendia of checklists for all possible intervention types. Rationalisation of checklists across topics and interventions is required without sacrificing the understanding of interplay between policy components, mechanisms and contexts that drives the endeavour. From an author's perspective, one approach may be to develop an online decision-tree that maps to the intervention checklist required, thus presenting authors with an easy-to-follow route to the correct checklist. We encourage the research community, and particularly those with an interest an evidence-based policy-making, to comment on our proposed checklist and collaborate to further efforts in these areas.Successful policy transfer from a study context to an implementation context can be facilitated by an improved understanding of similarities and differences in contexts across both time and place. Our proposed TRAICE checklist of context factors influencing population-level alcohol policy effectiveness illustrates how such an understanding might be gained. It offers potential for facilitating meta-regression and realist synthesis and also presents a route to ensuring that policy-makers have easy access to relevant contextual information when judging the transferability of evidence to their context.Research reported in this paper was funded by the Medical Research Council and Economic and Social Research Council (Grant G100043).


Although strategic thinking on water, sanitation and hygiene (WASH) has prioritized reducing exposure to human feces in order to limit diarrheal infections, recent research suggests that elevated exposure to livestock–particularly poultry and poultry feces–may be an important risk factor for diarrhea, environmental enteric disorder (EED) and respiratory infections, all of which may seriously retard linear growth in young children. Yet a very different literature on nutrition-sensitive agriculture suggests that livestock ownership is highly beneficial for child growth outcomes through its importance for increasing consumption of nutrient-rich animal sourced foods, such as eggs. Together, these two literatures suggest that the net nutritional benefit of poultry ownership is particularly ambiguous and potentially mediated by whether or not children are highly exposed to poultry. We test this novel hypothesis using a large agricultural survey of rural Ethiopian households that includes measures of child height-for-age Z-scores (HAZ), ownership of poultry and other types of livestock, and an indicator of whether livestock are kept within the main household dwelling overnight. We used least squares regression analysis to estimate unadjusted and adjusted models that control for a wide range of potentially confounding factors. We find that while poultry ownership is positively associated with child HAZ , the practice of corralling poultry in the household dwelling overnight is negatively associated with HAZ . Moreover, we find no negative associations between HAZ and corralling other livestock species indoors. These results suggest that while poultry ownership can be beneficial to child growth, overly close exposure to poultry poses a concurrent risk factor for undernutrition, most likely because of increased risk of infection. Child undernutrition in poor countries has long been linked to disease burdens such as diarrhea and respiratory infections, but more recently to environmental enteric disorder (EED), a sub-clinical condition characterized by chronic damage to the gut, malabsorption of nutrients and low level immune system stimulation that diverts resources away from growth and development –3. Both There are several reasons to reconsider the neglect of animal feces in the WASH, health/nutrition and agricultural sectors.First, exposure to animal feces may be more widespread than exposure to human feces in many parts of the developing world. Over 1990–2012, open defecation in the least developed countries fell from 45% to 20%, and in the world as a whole it fell from 24% to 14% . But in Second, a recent meta-analysis re-examined linkages between diarrhea in young children and exposure to animals . It founFinally, it has also been hypothesized that high concentrations of any bacteria–even non-pathogenic bacteria–in the small intestine can cause EED and stunting . So whilCampylobacter jejuni and E. Coli. In addition to this formative research, two papers from the Global Enteric Multicenter Study in the Mirzapur sub-district of Bangladesh linked EED and stunting with maternal reports of geophagy [Although biologically plausible, little research has examined the consequences of close exposure to livestock on child nutrition outcomes, even though over half of current and ongoing nutrition-sensitive agricultural projects include some form of livestock intervention . Exceptigeophagy  and keepgeophagy .In addition to this recent literature on the hygiene dimensions of livestock ownership, there is a re-emerging literature on the important of animal sourced foods (ASFs) for child nutrition in developing countries –25, as wIn this study we broach these two separate literatures by exploring the associations between household poultry ownership, exposure of children to poultry in the home, and child height-for-age Z-scores (HAZ) in a large multi-purpose household survey in rural Ethiopia. The context for this observational study, Ethiopia, is apt for several reasons. First, Ethiopia has rates of child stunting in excess of 40 percent  and low woredas).We use household survey data collected by the Central Statistical Agency of Ethiopia, with technical assistance from The International Food Policy Research Institute . This lA novel feature of the survey is that it allows us to link detailed agricultural production with children’s reported intake of food groups (dietary diversity) in the previous 24 hours and anthropometry. Anthropometric and dietary diversity data were collected for preschool children 0–59 months of age, amounting to a final sample of 3,494 children  after data cleaning. Length or height-for-age Z-scores (hereafter HAZ)–measured against World Health Organization norms –constituIn terms of livestock the FtF survey records ownership of different types of livestock types in addition to poultry. However, in earlier field visits we observed that while some household kept poultry in separate chicken coops/houses at night, many households keep poultry (and other livestock) in their main dwelling overnight, which may imply elevated levels of exposure to pathogens. Hence we requested the inclusion of additional questions to the FtF midline survey on whether any animals were kept inside the housing structure where household members sleep. This question results in indicators similar to those used in the Global Enteric Multicenter Study in Bangladesh , except At the same time, the dashed box and dashed arrows in Finally, while the objective of our empirical analysis is to test for negative mediation of children’s exposure to poultry, the FtF data set can also be used to engage in supplementary tests of whether poultry ownership increases children’s egg consumption. To test this we follow a similar analysis of cattle ownership, dairy consumption and child nutrition in rural Ethiopia . First, We begin our analysis with some descriptive analysis of nutrition, diets and animal husbandry in rural Ethiopia. Livestock ownership and housing practices are reported in In terms of anthropometric outcomes, In We also observe another significant difference across the sub-samples: "Poultry inside" households are more likely to keep other animals inside and own more livestock (perhaps because of common threats like predation or theft). These relationships are further explored in In regressions 3 and 4 we repeat the same exercise but adjust for the potential confounding factors listed in One other testable implication of the associations hypothesized in The remaining regressions in In addition to the results in Tables We also tested the robustness of the results in th, 50th, 75th quantiles to explore whether keeping livestock in the house had different impacts at different points in the conditional HAZ distribution . In scavenging poultry systems the flock tends to roam in and around the household dwelling (within 50 meters) during the day in pursuit of household food waste . As a reFinally, the results reported in Section 4 have important implications for programs and policies across several sectors. While it has been argued that egg consumption has significant potential to improve child nutrition outcomes in developing countries , the resS1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.


Soybean production is greatly influenced by abiotic stresses imposed by environmental factors such as drought, water submergence, salt, and heavy metals. A thorough understanding of plant response to abiotic stress at the molecular level is a prerequisite for its effective management. The molecular mechanism of stress tolerance is complex and requires information at the omic level to understand it effectively. In this regard, enormous progress has been made in the omics field in the areas of genomics, transcriptomics, and proteomics. The emerging field of ionomics is also being employed for investigating abiotic stress tolerance in soybean. Omic approaches generate a huge amount of data, and adequate advancements in computational tools have been achieved for effective analysis. However, the integration of omic-scale information to address complex genetics and physiological questions is still a challenge. In this review, we have described advances in omic tools in the view of conventional and modern approaches being used to dissect abiotic stress tolerance in soybean. Emphasis was given to approaches such as quantitative trait loci (QTL) mapping, genome-wide association studies (GWAS), and genomic selection (GS). Comparative genomics and candidate gene approaches are also discussed considering identification of potential genomic loci, genes, and biochemical pathways involved in stress tolerance mechanism in soybean. This review also provides a comprehensive catalog of available online omic resources for soybean and its effective utilization. We have also addressed the significance of phenomics in the integrated approaches and recognized high-throughput multi-dimensional phenotyping as a major limiting factor for the improvement of abiotic stress tolerance in soybean. Soybean is the most important legume crop which provides sources of oil and protein for human as well as for livestock. Soybean also enhances soil fertility because of the symbiotic nitrogen fixing ability. Soybean contributed to more than 50% of globally consumed edible oil  . This is due to the complex inheritance of abiotic stress tolerance which has identified unstable QTL across different environments. Further utilization of QTL information for marker-assisted breeding or candidate gene identification has become difficult due to this complexity. Statistical tools such as “Meta-QTL analysis” have been advanced that compile QTL data from different studies together on the same linkage map for identification of precise QTL region  mapping are marker based applications that have become more sophisticated with the availability of different genotyping platforms Table . ConsequQTL mapping using bi-parental populations has limitations because of restricted allelic diversity and genomic resolution. The allelic diversity can be increased to some extent by using multi-parental crosses. Recently, Multi-parent Advanced Generation Inter-Cross populations (MAGIC) has been used to identify QTL for blast and bacterial blight resistance, salinity and submergence tolerance, and grain quality traits in rice . These studies were performed with limited markers and genotypes. GWAS in soybean is lagging behind compared to maize, mostly because of the slow linkage disequilibrium (LD) decay . GS is relatively simple, more reliable, and a more powerful approach where breeding values of lines are predicted using their phenotypes and marker genotypes  has been observed among the genomic estimated breeding value (GEBV) and the phenotypic value. Another study published recently using 288 cultivars and 79 SSR markers, found a correlation coefficient of 0.90 among the GEBV and the phenotypic value . The increasing popularity of GS among plant as well as animal breeders is mostly because of the reduced cost of genotyping. Currently, GS is being used for breeding in several different crops (Table S3). In soybean, efforts have been made to evaluate GS using different models. A GS study in soybean has used 126 recombinant inbred lines and 80 SSR markers to predict primary embryogenesis capacity which is a highly polygenic trait  interaction but most of the studies focused only on an estimation of the main effect for each marker. These multi-environmental trials are of prime importance for plant breeding not only to study G × E but especially to increase the number of breeding cycles per year. The challenge for GS is to get accurate GEBV in respect to the G × E effect. Considering environmental effects is not new for plant breeders and most statistical models used for multi-location trials do reflect G × E . The microarray data represents various tissues, developmental stages, and environmental conditions  associated with a particular phenotype. However, QTL spans large segments of chromosomes and it is also the same for GWAS where LD decay is slow as in case of soybean  level need not be translated into differential amounts of protein. To address this, several proteomic studies have been performed to understand abiotic stress tolerance mechanisms in soybean (Table S4).Unexpected levels of changes in the soybean proteome can occur during stress response and these changes can lead to different defense mechanisms. Some common proteins involved in redox systems, carbon metabolism, photosynthesis, signaling, and amino acid metabolism have been found to be associated with various stress responses in soybean . Volunteer deposition of proteomic information in such databases is necessary for effective utilization of available knowledge for the management of abiotic stress tolerance in soybean.In the near future, various proteomics approaches will be routinely used in soybean research that will generate tremendous information regarding structural and functional attributes of proteins. A systematic cataloging of information in the form of a publically accessible database is very important. Recently, a proteome database has been developed that contains reference maps of the soybean proteome collected from several organs, tissues, and organelles . Development of new chromatographic and mass spectrometric platforms along with the enhancement of operational and analytical capabilities of existing platforms revolutionizes metabolomic investigations both in plant and animal sciences. The platforms such as gas chromatography mass spectrometry (GC-MS), fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS), liquid chromatography mass spectrometry (LC-MS), capillary electrophoresis mass spectrometry (CE-MS), and nuclear magnetic resonance (NMR) are routinely used in plant sciences  and potassium (K) are the two key elements used as macronutrients in fertilizer to ensure better crop yield. However plants require many other elements and those are not uniformly distributed among different soil types. Plants have evolved with a diverse element uptake ability at different locations because of diverse soil types  is used to understand biological status, such as disease, pest infestation or physiological disorders. With technological advances, genomic resources have been routinely used to predict phenotype based on the evaluation of genetic markers; it can be called “genetic symptoms.” The success of genomics is based on how reliable connection is there between a genetic marker and the phenotype. In plant breeding, genetic improvement through omics approaches is being conducted to achieve ideal phenotype that will ensure higher and stable yield under diverse environmental conditions. Therefore phenomics integrated with other omics approaches has the most potential in the plant breeding Figure .www.lemnatec.com). However, these platforms have not gained the expected popularity even though tremendous advancement in both imaging as well as robotic technology has been achieved.Phenome has a broader meaning than what is being generally considered. It is not limited to the visible morphology of an organism but expectedly larger and complex. Unlike genomics, where the entire genome can be characterized by sequencing, the phenome cannot be characterized entirely. Therefore, the term phenomics being an analogy to genomics expected only study of particular set of phenotype at high-throughput level and not the entire set. In this regards, the technological development in image processing and the automation techniques have played important roles. Plant imaging with light sources from visible to near infrared spectrum provides an opportunity for non-destructive phenotyping. Therefore, real-time analysis of plant development became possible. Moreover, robotic technologies used in phenomic platforms have increased the precision and speed of phenotyping. This has allowed for incorporating additional aids such as precise irrigation and fertilization systems. For instance, “PHENOPSIS” an automated phenomic platform has been developed to study water stress in Arabidopsis and has a robotic arm loaded with a tube for irrigation and a camera . Recently, a method has been developed to assess leaf growth in soybean under different environmental conditions . The 1000 genome project will generate a huge amount of genomic information which will require utilization of comparable phenomic data. This will be helpful to accelerate soybean research in many ways.Phenomics in soybean is lagging far behind genomics because hundreds of genomes and many genetic populations are re-sequenced. One best example is the 1000 genome re-sequencing project at the University of Missouri, MO, USA (http://soykb.org) is a very useful database that provides a comprehensive web resource for omics data from several different platforms (Joshi et al., The recent advancement in the omic platforms has generated tremendous information which has been used to promote research activities in all possible dimensions. Utilization of available information has become possible because of computational resources that helps to catalog, store, and analyze available data and make it easily accessible through user friendly interfaces so called “databases.” In this regard, several databases have been developed for soybean Table . Among tDifferent omics tools have been employed to understand how soybean plants respond to abiotic stress conditions. We realize that the studies to integrate multiple omics approaches are limiting in soybean due to the increased cost and potential challenging integrated omic scale analysis. Recent developments in computational resources, statistical tools, and instrumentation have lowered the cost of omics in many folds but integrated analysis needs novel tools and technical wizards. The comprehensive nature of multi-omic studies provides an entirely new avenue and future research programs should plan to adapt accordingly. In soybean, genomics and transcriptomics have progressed as expected but the other major omic branches like proteomics, metabolomics, and phenomics are still lagging behind. These omic branches are equally important to get clear picture of the biological system. Notably, phenomic studies need to be extensively employed along with the other omics approaches. Desired phenotype is ultimate aim of crop sciences; therefore it needs to be understood intensely. Different omic tools and integrated approaches discussed in the present review will provide glimpses of current scenarios and future perspectives for the effective management of abiotic stress tolerance in soybean.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.


Sensing gravity is vital for our perception of spatial orientation, the control of upright posture, and generation of our everyday activities. When an astronaut transitions to microgravity or returns to earth, the vestibular input arising from self-motion will not match the brain's expectation. Our recent neurophysiological studies have provided insight into how the nervous system rapidly reorganizes when vestibular input becomes unreliable by both (1) updating its internal model of the sensory consequences of motion and (2) up-weighting more reliable extra-vestibular information. These neural strategies, in turn, are linked to improvements in sensorimotor performance  and perception characterized by similar time courses. We suggest that furthering our understanding of the neural mechanisms that underlie sensorimotor adaptation will have important implications for optimizing training programs for astronauts before and after space exploration missions and for the design of goal-oriented rehabilitation for patients. On earth, gravity provides a unique reference axis to which we can anchor our body orientation and monitor orientation changes. Indeed, as Lacquaniti et al.  have notThe effects of this decrease in gravity are most pronounced immediately after the transition to microgravity  such that astronauts are able to comfortably make voluntary head movements during a mission. Astronauts again experience these symptoms upon returning to Earth's 1-g environment. Because access to astronauts is more straightforward in this latter condition, it is more often the focus of quantitative studies. Interestingly, aspects of the motor performance observed after returning to 1-g environment astronauts are similar to those observed in the patients from acute unilateral vestibular peripheral loss  at the level of the single neurons that constitute the first central stage of vestibular processing. At least two types of extravestibular inputs can substitute for the lost vestibular input, (1) proprioception and (2) motor efference copy signals. As reviewed above, in normal conditions, vestibular responses to active motion are suppressed when there is a match between the brain's estimate of proprioceptive feedback and the actual sensory feedback. However, under normal conditions (1) passive stimulation of neck proprioceptors in isolation does not alter neuronal responses and (2) the generation of motor efference copy signals does not alter neuronal responses when the head is prevented from moving . In contrast, following peripheral vestibular loss, neurons respond differently. First, robust response to passive stimulation of neck proprioceptors are rapidly unmasked in the early vestibular pathway Figure . FurtherThe time course of the dynamic re-weighting of multimodal information observed at the level of single neurons, follows a similar time course to the improvement observed in (1) patient performance following vestibular loss and (2) astronaut return back to earth Figure . Early sRecently, we have further demonstrated that, following partial vestibular loss, neurons at the first central stage of vestibular processing, in the vestibular nuclei, show increased variability in response to vestibular stimulation. This increase in variability does not improve over time and ultimately constrains neural detection thresholds  appears to involve the simultaneous updating of internal models and the dynamic re-weighting of multimodal input. We speculate that the central nervous system utilizes a similar multimodal strategy to compensate for changes in gravity, experienced in both of these conditions. Our recent neurophysiological findings further provide a neural correlate for the benefits provided by rehabilitative strategies that take advantage of the convergence of multisensory cues during sensorimotor adaptation following vestibular loss. For example, standard rehabilitation techniques aimed at improving balance such as Cawthorne–Cooksey exercises incorporate the generation of head and body movements, which essentially provides multimodal stimulation (i.e., combined vestibular and proprioceptive; reviewed in Ricci et al., 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 modern-era abdominal compartment syndrome (ACS) was first described as a ‘new’ clinical entity in the 1980s in emergency surgery patients, despite being described over 100 years earlier . SimultaAlthough controversial initially, IAH is now widely accepted as a cause of organ dysfunction and ACS is recognized as a catastrophic disturbance of a patient’s physiology that requires urgent intervention and guided therapies . Over thIAH does not only affect abdominal organs – raised IAP affects the different organ systems ; it greaImproved insights into the pathophysiology and causes of IAH and ACS have led to improved management of patients at risk . Open abWhereas the incidence of end-stage, highly lethal, overt ACS is decreasing, IAH persists and is likely to increasingly do so as critically ill patients increasingly survive initial insults. Better understanding of the risks associated with IAH is thus necessary, as well as recognizing clinically important thresholds  and critOne of the major challenges currently in our ICUs is the management of open abdomen patients. An open abdomen is at high risk of a myriad of complications and planning for a safe same-admission closure begins immediately after opening . It has As a highly focused specialist society, the World Society of the Abdominal Compartment Syndrome (WSACS) has been assisting healthcare workers to better understand IAH and ACS; the WSACS’s efforts have certainly contributed to many advances that have been made in the past . As ACS WSACS – the Abdominal Compartment Society remains a dedicated multidisciplinary international society of clinicians, scientists, clinician-scientists, and other healthcare workers dedicated to understanding the holistic implications of IAP. Further, the society understands and promotes health through championing anatomically functional abdominal compartment reconstruction at the earliest time after critical illness/injury, balancing the needs at all times for physiologic decompression and avoidance of IAH with anatomic reconstruction.Understanding the subtle implications of modest IAH on all critically ill/injured patients and especially validating potential therapeutic interventions with new sound evidence remain our biggest challenges. A new emphasis will be placed upon embracing those engaged in the emerging surgical subspecialty of abdominal wall reconstruction. Ultimately, complete integration of these findings in the management of patients with relevant abdominal conditions affected by IAH remains the final goal.In conclusion, IAH and ACS have evolved from poorly understood and inconsistently diagnosed disorders. Overall, ACS is decreasing through early recognition and directed management of IAH. In this context, WSACS – the Abdominal Compartment Society will continue its educational activities, support research, and promote evidence-based guidelines in order to continue to improve outcome in critically ill patients.


In spite of many data gathered during the last two decades on adult neurogenesis (AN) it is evident that such knowledge is not sufficient for granting translational outcomes in brain repair, especially if the ultimate goal is to promote cell replacement. Alternative strategies aimed at fostering AN physiological functions (restorative approaches) are still undefined. By asking the question whether AN research field has to be considered as a dead end in the context of brain repair, here we review some unresolved issues: multifaceted evolutionary constraints in mammals, stem/progenitor cell type/availability and tissue permissivity, impact on other brain functions, interplay with other forms of plasticity, and relevance in humans. We suggest that full understanding of AN biology is an essential step for its possible exploitation in brain repair, and that further fundamental, multidisciplinary research is required to reach translational outcomes. Scientist's attitude and their communication skills are also important. To avoid overestimation of AN reparative potential in a translational perspective, more distant goals of cell replacement should be kept clearly distinct from restorative approaches involving AN functional plasticity. Two decades of investigation on adult neurogenesis (AN) yielded an utterly new vision of brain plasticity and opened new perspectives for brain repair/regeneration strategies. Nevertheless, the ultimate goal of exploiting neurogenic processes for obtaining cell replacement is still far from being achieved. Starting from this antinomy, the big question is: should be the AN research field considered as a dead end in the perspective of brain repair, or, alternatively, is it worthwhile to put in place further efforts in order to solve the problem? By reading the scientific literature, it is clear that all neurobiologists, even believing in an AN translational future, do not share the same answer. Non-univocal visions are normal in a field that has developed by progressively ramifying in many directions accordingly to the different goals pursued by each research group. Some scientists primarily deal with AN physiological roles/mechanisms, apparently being less interested in direct translation of results. Others are mainly focused on aspects that implement AN, or directly address the issue of injury-induced, reactive neurogenesis, paying less attention to the peculiar limits of the mammalian CNS in repairing damage. New translational perspectives in “restorative” rather than “structural reparative” neurology have been recently raised, what could be useful in slowing down the impact of various neurologic impairments , even in the absence of cell replacement. Nevertheless, it is evident that knowledge gathered during the last two decades is not yet sufficient for granting translation of basic neurobiological research. Such inability is linked to several unresolved issues in both physiological and lesion-induced neurogenesis, and to scarcely integrated views between different approaches used to address AN studies. In other words, even in the absence of current, effective therapeutic outcomes, we may not be at a dead end, rather we are in the middle of a route with many new “perfectly reasonable deviations from the beaten track” Feynman, .Our knowledge of AN in mammals might be grouped in two domains: first, some facts and concepts which are definitively accepted and substantially understood by the scientific community (“acquired knowledge”), and second, a number of issues which remain largely obscure and/or underestimated (“gaps of knowledge”). The main blocks of acquired knowledge can be summarized as follows: (i) two canonical neurogenic zones  harboring stem cell niches provide neural cell addition into the olfactory bulb and hippocampus . The main aspects that seem essential in granting CNS neurogenic/reparative capacity are: occurrence of specialized progenitor types and tissue permissivity. The SVZ and SGZ neurogenic niches harbor stem cells that appear very specified in their commitment , it should be emphasized that it is only one among other forms of CNS plasticity and that very little is known about the mechanisms which underlie their mutual relationships.The CNS of mammals, in spite of having lost most of its regenerative/repair capacity with respect to other phyla, is endowed with different forms of structural plasticity involving pre-existing cellular elements , although further technical advancements are needed (e.g., cell imaging enhanced resolution; Sierra et al., It appears evident that having introduced excessive and premature translational issues toward brain repair did not solve the problem of neurological diseases. Moreover, a simplistic view of AN as a ready-made therapeutic tool could even be counterproductive, since it might put down the interest in AN studies. In spite of some oversights along the route, the increasing knowledge gathered during the last 20 years is enormous, considering the changes that AN research has produced in our vision of brain plasticity. Non-invasive technologies are essential to study AN in humans (e.g., Spalding et al., 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.


Manduca sexta, as much is known about the natural behaviors related to host plant selection and the involved neurons at several level of the sensory pathway. We also discuss how herbivore-induced plant odorants and secondary metabolites in floral nectar in turn can affect moth behavior, and the underlying neural mechanisms.Understanding how animals make use of environmental information to guide behavior is a fundamental problem in the field of neuroscience. Similarly, the field of ecology seeks to understand the role of behavior in shaping interactions between organisms at various levels of organization, including population-, community- and even ecosystem-level scales. Together, the newly emerged field of “Neuroecology” seeks to unravel this fundamental question by studying both the function of neurons at many levels of the sensory pathway and the interactions between organisms and their natural environment. The interactions between herbivorous insects and their host plants are ideal examples of Neuroecology given the strong ecological and evolutionary forces and the underlying physiological and behavioral mechanisms that shaped these interactions. In this review we focus on an exemplary herbivorous insect within the Lepidoptera, the giant sphinx moth  Herbivory is a major evolutionary achievement in eukaryotic animals and in particular in insects, with nearly half of all existing species feeding on living plants Gilbert, . LepidopZyraphera diniana having different host preferences , as we know much about both the anatomical and functional organization of its chemosensory system and about the olfactory cues that guide host finding in this crepuscular/nocturnal insect.In this review we focus on the neural mechanisms underlying host plant selection by moths in a “Neuroecological” context, that is, the function of neurons in an adaptive biologically relevant framework. Almost all of what we review here draws from studies in the exemplary giant sphinx moth M. sexta. Both sexes of this nocturnally active insect must find flowers on which to feed, males must find females, and gravid females must find the proper host plants on which to lay their eggs. A particularly well characterized olfactory-guided behavior of adult M. sexta (as well as of many other moth species) is the oriented flight response of males to the sex-pheromone blend released by conspecific females , native and cultivated species of tobacco (Nicotiana sp.), tomato, eggplant, pepper, etc.,  induces both direct and indirect defenses  for plants, it can reduce the probability of secondary attacks and provide host cues for the natural enemies of the herbivores, while providing information to and from neighboring plants; and (2) for the herbivore, it provides information about the suitability of the host plant with regards to its chemical defenses and its metabolic and physiological health.Insect herbivores are agents of selection on plant defense traits because plant populations excluded from herbivory evolve lower resistance and higher competitive ability, but these populations can quickly regain increased resistance when re-exposed to the herbivore  did not significantly increase floral volatile production  damaged by the same herbivore the floral blend significantly differed from that of non-damaged plants , each of which contains one or a few olfactory sensory neurons (OSNs) , and the axons of OSNs expressing the same OR converge on the same glomerulus . The labial palps of moths of both sexes also have OSNs that respond to changes in ambient CO2, a cue that is important in moth behavior, and converge in a single glomerulus in each AL  and projection neurons  . While moths in these two families shared some  foraging and oviposition characteristics, the basic AL mapping of host plant odorants was comparable across species. Thus, these results demonstrate that similar coding strategies are used even by families separated more than 65 million years ago , more sensitive to (−)-linalool than to (+)-linalool -linalool has an important role in mediating oviposition attraction. In contrast, we found that plants with (−)-linalool added are avoided by ovipositing females Figure , and thaAlthough linalool has important roles in mediating oviposition, it is very likely that the choice of suitable host plant sites is mediated by a suite of VOCs. A powerful technique to address this issue, which has been already used to investigate the VOCs involved in mediating feeding  can elicit feeding  to deter herbivores and pathogens  and the effects of herbivory , female moths encounter resources that are spatio-temporally patchy. The moth nervous system has the ability to adjust its activity so that behavioral output is maximally beneficial for survival within an often harsh and patchy environment. This plasticity is accomplished by the release of specific neuromodulators—including serotonin, octopamine and dopamine—within restricted brain regions like the AL, the lateral horn and the mushroom bodies. For example, herbivory-induced damage to D. wrightii plants elicits high concentrations of certain alkaloids in the flower nectar which M. sexta finds aversive. Tropane alkaloids (including scopolamine) in the nectar of damaged D. wrightii increase more than 20-fold in damaged plants . Furthermore, some of these volatiles also mediate behavior in distant moth species, suggesting important roles for certain plant volatiles and commonalities in their neural processing. In addition, for the plant benefit, plant secondary compounds can affect host-plant finding and behavior through processes such as learning and memory.Here we used an exemplary specialized herbivorous insect, the moth M. sexta and other insect species, many issues, at several levels of interactions, need to be addressed. For instance, do different populations of host plants differ in their VOC profile, and what are the behavioral consequences? Given that M. sexta is found throughout a wide range in the American continent, is there a common set of VOCs that guide oviposition choice, despite that moths across the distribution range use different host plant species? Is there a minimum VOC blend that produces acceptance and egg lying? Would this blend suffice to guide oviposition choice in different moth populations? Are populations in other regions as specialized in certain host plants as the Southwest USA population? Do background odors affect olfactory-guided oviposition choices? Do other other factors such as temperature and humidity affect host plant choice? In nature, do females actually avoid ovipositing on plants where other larvae are already present, and if so, how do they achieve this? An interesting possibility, given that M. sexta host plants naturally produce alkaloids which can be readily detected by moths (Bernays et al., While today we have a deeper understanding of how the nervous system process information about behaviorally relevant VOCs in Finally, along with a deep understanding of the relationships of organisms with their natural environment, we believe that in the near future genomic tools now available to many insect species will permit a deeper and more complete understanding of how the insect nervous system produces adaptive behavior.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.