Understanding the molecular network of orderly mitotic exit to re-establish a functional interphase nucleus is critical because disordered mitotic exit inevitably leads to genomic instability. In contrast to the mechanisms of the entrance to mitosis, however, little is known about what controls the orderly exit from mitosis, particularly in mammalian cells. The chromosomal passenger complex (CPC), which is composed of Aurora B, INCENP, Borealin and Survivin, is one of the most widely studied and highly conserved hetero-tetrameric complexes. The CPC orchestrates proper chromosome segregation with cytokinesis by targeting to specific locations at different stages of mitosis. Recent studies reveal that controlling CPC localization and Aurora B kinase activity also serves as a key surveillance mechanism for the orderly mitotic exit. This ensures the reformation of a functional interphase nucleus from condensed mitotic chromosomes by delaying mitotic exit and cytokinetic processes in response to defects in chromosome segregation. In this review, we will summarize the latest insight into the molecular mechanisms that regulate CPC localization during mitotic exit and discuss how targeting Aurora B activity to different locations at different times impacts executing multiple mitotic exit events in order and recently proposed surveillance mechanisms. Finally, we briefly discuss the potential implication of deregulated Aurora B in inducing genomic damage and tumorigenesis with current efforts in targeting Aurora B activity for anti-cancer therapy. For accurate cell division, an exact copy of the genome must be equally transmitted from a mother cell to two dividing daughter cells. This requires equal segregation of the duplicated sister chromatids during mitosis followed by cytoplasmic division involving cytoskeletal reorganization and membrane scission events. These processes are tightly orchestrated by the opposing activities of protein kinases and phosphatases on mitotic chromosomes and in the cell equator, which includes the spindle midzone and the equatorial cortex. Such opposing activities are also likely present in the midbody to complete cytokinesis.The dynamic localization of chromosomal passenger proteins in the proper time and space predicts the molecular connections of chromosome segregation and cytokinesis. These two events can be orchestrated by a set of master regulators, which are localized to a mitotic chromosome prior to its segregation but thereafter transferred to the cell equator for cytokinesis , and finally in the midbody, the CPC controls the timing of abscission that completes cytokinesis  binding to INCENP  -mediated phosphorylation of Ipl1/Aurora B suppresses its association with the microtubule plus-end tracking protein Bim1, which is a homolog of end-binding 1 (EB1). This also inhibits Ipl1/Aurora B localization to the spindle midzone before anaphase onset  resulted in the recruitment of mitotic checkpoint proteins, including Mad1, BubR1, and Bub1, to the anaphase kinetochore  because segregation of sister chromatids and APCCdc20-mediated cyclin B degradation occur with normal kinetics without affecting the stability of mitotic spindles attached to the kinetochores   that directly bind and inhibit tubulin have been appreciated for quite some time. Dividing tumor cells need dynamic microtubules to divide, explaining why the anti-microtubule drugs are effective against cancer cells. However, because microtubules are also required for numerous other cellular functions, the anti-microtubule drugs are often toxic to both dividing and non-dividing normal cells. Another common cytotoxin, including DNA damaging drugs, a typical toxicity toward normal dividing cells, is myelosuppression, which is generally reversible and therefore clinically manageable. However, atypical side effects associated with anti-microtubule drugs include peripheral neuropathies, caused by the inhibition of microtubule-dependent processes in neuronal axons and glial cells. Notably, clinically relevant concentrations of paclitaxel cause death in interphase only after a perturbed mitosis , as a single agent in acute myeloid leukemia (AML) (Löwenberg et al., In proliferative cancer cells, treatment with Aurora B inhibitors induces failed cytokinesis that produces enlarged polyploid cells with multiple centrosomes. After removing drugs, it is expected that these cells proceed to mitosis in a highly uncoordinated manner, leading to unrepairable chromosomal damages and subsequent cancer cell death. Indeed, Aurora B inhibitors are highly effective at killing cancer cells Mitotic exit is a complex transition involving many dramatic cellular changes to occur in a coordinated manner. For instance, the premature decondensation of sister chromatids, before they are sufficiently removed from the ingressing cleavage furrow, causes chromosome missegregation and breakage. Such defects lead to micronuclei formation, chromosome rearrangement and DNA damage that are often found in human solid tumors. In addition to what it was known about the formation and ingression of the cleavage furrow during cytokinesis after relocating to the cell equator, the emerging view is that the CPC extensively functions in safeguarding genome integrity by monitoring the mitotic exit events so they are executed in an orderly manner. The recently proposed Aurora B-mediated checkpoints during mitotic exit and cytokinesis require further validation, but it is clear that targeting the CPC to different locations at different times during mitotic exit provides dividing daughter cells with a versatile surveillance system to re-establish a functional interphase nucleus. Future research is needed to investigate whether the CPC actively senses and signals to repair certain abnormalities of segregating sister chromatids or only passively delays an improperly executed mitotic exit event. It also remains to be determined how the CPC integrates and translates multiple phosphorylation events to determine the timing of abscission. Furthermore, the phosphatases and the regulatory subunits that counteract Aurora B activity at specific locations with defined substrate specificity are beginning to emerge, particularly before mitotic exit. Clearly, the correct balance between Aurora B and its counteracting phosphatase activities in time and space must also be crucial for regulating proper mitotic exit and completion of cytokinesis, which is an important topic for future research.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.


Recent advances in quantitative LC-MS/MS based proteomics have made possible the reliable quantification of thousands of phosphorylation peptides in eukaryotic cells  is typically carried out for a specific PTM prior to subsequent MS analysis. The enrichment steps are however, for many, a major drawback in bacterial PTM analyses, since the enrichment step typically requires large amounts of starting material including protein concentrations in the order of 5–9 mg , and parallel reaction monitoring (PRM), appear as perhaps the latest breakthrough within the field. Specifically, targeted mass spectrometry offers unequaled capability to characterize and quantify a specific set of proteins/peptides reproducibility, in any biological sample. In this hypothesis-driven approach . Thus, in order to gain meaningful insights into the dynamics and role of different bacterial PTMs during host-pathogen interactions, it is crucial that researchers in the field join efforts to once again take advantage of recent advances in mass spectrometry instrumentation and develop targeted, quantitative PTM workflows that enable detection and accurate quantification of low-abundance, modified analytes, ideally circumventing the need for additional PTM enrichment steps in the process.Targeted methodologies have been successfully applied to investigate aspects of the pathogenic bacteria proteome . The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflicts with subject matter or materials discussed in the manuscript.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.


Root–root interaction research gained more and more attention over the past few years. Roots are pivotal for plant survival because they ensure uptake of water and nutrients. Therefore, detection of adjacent roots might lead to competitive advantages. Several lines of experimental evidence suggest that roots have ways to discriminate non-related roots, kin, and—importantly—that they can sense self/non-self roots to avoid intra-plant competition. In this mini-review, the existence of self/non-self recognition in plant roots will be discussed and the current knowledge on the mechanisms that could be involved will be summarized. Although the process of identity recognition is still not completely understood, interesting data are available and emerging new technologies will certainly aid to better understand this research field that can have an important biological, ecological, and agricultural impact. Competition among coexisting plants—most restrictively defined as a negative interaction among individuals with reduced growth, survival, or fecundity of neighbors as a consequence —is all aRoots are pivotal for plant survival because they ensure the uptake of nutrients and water and they secure fixation in the soil; hence, the growing interest in the study of belowground plant competition. Plants that grow together in one soil volume depend on the same resources and rearrange their root systems to gain access to these limited supplies . Indeed,Here, knowledge on root–root dynamics between interacting plants will be summarized and new advances will be discussed that cannot only enhance the understanding of plant evolution and biology, but can also have an impact on ecology and agriculture.Parthenium argentatum  trees  roots that exclude Solanum lycopersicum (tomato) roots (Fragaria vesca (wild strawberry) roots are drawn to Glechoma hederacea (ground ivy) roots, whereas the ivy roots avoid the strawberry roots (Fragaria chiloensis (beach strawberry) roots is stimulated upon contact with ground ivy (Glycine max (soybean) and Allium cepa  and soybean species are grown together, the roots of each plant tend to keep away from each other and become shallower than those in systems intercropped with their kin. Remarkably, not every maize variety responds in the same manner to the presence of the same soybean species (Beta vulgaris (beet) variety grow faster and deeper than legume roots grown in the same soil, providing a competitive advantage  trees intercropped with Sorghum bicolor (sorghum) is also higher than that of monocultures (Cakile edentula (sea rocket) and Impatiens pallida , root allocation is larger and smaller in groups of strangers than of siblings, respectively  trees , or inteo) roots . Roots cry roots . In addiound ivy . Analysiound ivy . In cropa onion; , but als species . Similardvantage . Furtherdvantage . The roocultures . Intriguectively . In concectively  vary in In plants, identity recognition has been unequivocally demonstrated for several biological processes that affect plant fitness, reproduction, and/or survival. For instance approximately 60% of the angiosperms show self-incompatibility which ultimately serves to prevent self-fertilization . Roots of Ambrosia stop growing when root systems from other Ambrosia plants  are encountered, seemingly as an avoidance response, but not when roots from the same physiological individual  are sensed (Larrea tridentata (creosote bush), also a desert shrub, tolerate neither other Larrea nor Ambrosia roots in their proximity  and Buchloe dactyloides  plants and for Centaurea maculosa  with the same input of water and nutrients . MoreoveArtemisia tridentata (sagebrush) increase herbivore resistance when compared to volatiles from non-self cuttings . Exclusion of aerial interactions by shoot separation experiments hinted at the induction of interactions by root exudates that diffuse into the medium rather than by physical contact (Deschampsia cespitosa (tufted-hair grass), root exudates have also been demonstrated as cues of neighbor identity that control root mass and morphology  clearly indicate that sensing neighboring roots occurs before resource depletion is discovered , and soybean interactions. As a drawback, genetically modified plants are required that, hence, hamper ecological applications. These non-destructive technologies outcompete the mere analysis of root biomass and are promising alternatives for root–root interaction and root identity recognition studies.Moreover, quantification of belowground interactions is difficult, certainly at the level of the individual root. Although beyond the scope of this minireview, recent advances in imaging technology might be helpful. A transparent gel system is now developed that allows imaging and three-dimensional reconstruction to quantitatively assess root growth parameters during interaction studies . Likewisin planta, as well as molecular biological approaches should be utilized to clarify root–root identity recognition. The obtained results can have an enormous impact on the research in plant biology and development as well as on the agricultural and ecological research fields and practice.In conclusion, exciting advances in the field of self/non-self recognition of roots have been made over the recent years. New imaging technologies will not only aid to analyze the root response in a non-destructive way, but will also allow kinetics studies that will help to understand the mechanisms of root identity recognition and to avoid the confusion of the effects of root interactions with those of nutrients and root volume. The identification of a core set of genes involved in neighbor detection merits further research and functional analyses. New and high-resolution chemical analysis techniques, besides state-of-the-art techniques used to measure electrical signals The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The use of meshes has become the first option for the treatment of soft tissue disorders as hernias and stress urinary incontinence and widely used in vaginal prolapse's treatment. However, complications related to mesh issues cannot be neglected. Various strategies have been used to improve tissue integration of prosthetic meshes and reduce related complications. The aim of this review is to present the state of art of mesh innovations, presenting the whole arsenal which has been studied worldwide since composite meshes, coated meshes, collagen's derived meshes and tissue engineered prostheses, with focus on its biocompatibility and technical innovations, especially for vaginal prolapse surgery. Soft tissue surgery has become the most common surgical procedure in western countries as a result of population aging as well as over-weight and obesity increasing . On thisPOP's pathophysiology remains unclear. The strength of the pelvic floor depends on the interplay of properly innervated muscles, ligaments, and connective tissue. The etiology of prolapse is likely multifactorial, developing from obstetric trauma and denervation to the pelvic floor, as well as altered collagen and connective tissue metabolism in pelvic floor tissues .Polypropylene (PP) materials became one of the most popular meshes implanted for soft tissue repair  due to fDespite its popularity, complications related to mesh issues cannot be neglected, including infection and exposure of the prosthesis or erosion of vaginal wall for transvaginal implantation . Many ofTo improve the outcome of surgical treat-ment of POP, different types of surgical implants have been launched over the last decade  and variThe aim of this review is to perform a literature review of the state of the art on mesh's use for vaginal prolapse surgery focused on its biocompatibility and technical innovations.Online searches through Pubmed, Embase and Web of Science were conducted using the search terms “mesh(es)”, “biomaterials”, “innovations“, “urinary incontinence”, “prolapses”, “biocompatibility” and “integration”. Priority was given to publications within the past 5 years in English language. Abstracts were reviewed and 58 studies were selected and subsequent suitable full texts manuscripts obtained. Of those, 7 studies were excluded for presenting data only related to hernia's treatment and 3 studies were excluded due to the lack of a reliable description of methodology. The level of evidence of each study is presented.It is worthy to define mesh biocompatibility to better understand which strategies have recently been developed and tested for reducing complications and improving clinical results. It is basically determined by the foreign body reaction (FBR) and is totally connected to mesh integration.The highly dynamic process of the FBR is considerably influenced by the biomaterial composition and its specific features. For instance, it has been well established in the literature that monofilament polypropylene mesh with large porous elicits a more biocompatible FBR resulting in better integration than multifilament and small porous size. Amid  devised Graft options have evolved over years, and include autografts, allografts, xenografts and synthetic materials . SurgeonModifications of the polymer's chemical composition, material weight, filament structure and pore size have substantial effects in the in vivo biocompatibility and are potential parameters to be studied in order to improve clinical results.We have didactically divided researches into 5 topics that will further be presented:Composite MeshesChanges In Mesh Density And Pore SizesCoating BiomaterialsCollagen Derived BiomaterialsTissue Engineered Protheses (TEP)Theoretically, the rationale of using a composite mesh is to associate an absorbable component, which will reduce the amount of foreign material in the host without compromising the mechanical resistance in the end of the integration process. Moreover, absorbable components can act as a long lasting dressing during healing period , 12. RecClinical studies using polyglactin have already been published. In 2001 Weber et al.  comparedExperimental studies about this subject are also available. Junge et al., in an experimental study using 60 male Sprague-Dawley rats, found benefits of using a partially absorbable (PG+PP) mesh in terms of a reduced amount of biomaterial after implantation and absorption of the absorbable part when compared with a standard non––absorbable PP mesh  (LE: 5).A hybrid mesh (HM) composed of polypropylene mesh embedded in a polysaccharide hydrogel was studied after intramuscular and subcutaneous implantation in rats in comparison with two clinically used materials. Histological and mechanical aspects were analyzed and the authors concluded that HM's use is promising because it is easy to make, easily implanted, and once inserted produces little foreign body reaction, creating a well-balanced integration with the tissue environment. Further, using the properties of this hydrogel to deliver substances locally  can be used to regulate tissue colonization  (LE: 5).Theoretically, low-density meshes would optimize the FBR by reducing the mass of the material used and diminishing its contact interface with the host tissue . HoweverBiomaterial surface properties play an important role. The use of some agents for coating biomaterials is based on their ability to mask the underlying surface by producing a hydrophilic interface. These coating layers improve the device/ host tissue interactions and consequently improve device functionality and life span , 23. VarAs therapeutic drugs, corticosteroids have been used for their immunosuppressive benefits in daily practice for decades. Recent emphasis on their effects on tissue remodeling and fibrosis in FBR underline their therapeutic potential . Brandt Animal experiments support the hypothesis that autologous modification of alloplastic materials by coating with plasma leads can improve early integration of the respective material into the different locations. Gerullis et al.  implanteTitanium is considered to be an inert material and has been used for decades in orthopedic and dental implants. As a coating, it is thought to resist to degradation at room temperature due to a thin and stable protective oxide layer that forms on its surface.Titanium-coated PP meshes have more recently come into use in the field of pelvic re-constructive surgery and hernia repair. However, studies of titanized meshes used for hernia repair in animal models have not clearly shown any superior benefit, with no significant differences  or even Prudente et al.  impregnaAn anti-infective drug-eluting mesh that slowly delivers antibiotic around the surgical site could be used to avoid bacterial contamination of the prosthesis and subsequent biofilm formation. The local delivery system offer several advantages over systemic administration: greater efficacy, lower drug dose required, less toxicity due to the lo-cal release of the drug, extended activity and less likelihood of promoting antimicrobial resistance , 34 LE: (LE: 3).For many years, silver has been a precious metal that is used in several fields of medicine and surgery for its anti-infectious properties . A studyCollagen-based biomaterials have been available for several decades and are becoming increasingly popular due to their perceived biocompatibility and low immunogenicity .Collagen type I has been used as a coating for polypropylene mesh because of its unique bio-logical properties. It is the most abundant protein in the mammalian connective tissues. Its structure is very conservative and therefore it does not induce an immune reaction even if a xenogeneic material is used. It enhances and augments growth of mesothelial cells that act as an antiadhesive layer . Some reTM) versus collagen-coated PP mesh (PelvitexTM) at 12 weeks and found similar scores for inflammation, neovascularization, and fibroblastic proliferation, but a higher apoptotic activity in the collagen-coated group  (LE: 5). De Tayrac et al. used a sheep vagina model  na model  (LE: 2).In an experimental study, PP mesh coating with a new highly purified collagen gel consisting of type I collagen obtained from bovine tendon was implanted in a rat model and showed an in-crease of adherence of the mesh to the neighboring tissue, less intense and persistent lymphocyte, plasma cell, and granulomatous reaction and a higher birefringence level of the collagen fibers, thus reflecting an improved molecular organization of newly formed collagen and a positive re-modeling action in mesenchymal repair involving polypropylene mesh  (LE: 5) Porcine small intestinal submucosa (SIS) is an almost acellular biomaterial, which is derived from the submucosal layer of pig small intestine and exhibits several characteristics that are advantageous for sling placement: its extracellular matrix promotes ingrowth of cells that remodel it into functional host tissues; its cytokines attract host cells and promote angiogenesis; it is strong, easily sutured, and can be easily manufactured to match the physical properties of the tissue being replaced; and elicits only a mild immunologic response . In a coRecent advances in cell-based technology using regenerative medicine techniques suggest that this approach holds enormous potential to improve human conditions by encompassing alteration of the current biological state of a targeted tissue, augmentation of depleted function, or absolute functional tissue replacement . To thatThe potential use of cell-based tissue engineering strategies to treat POP appears to be more intricate. The vagina is a complex organ with great demands of functionality, and parameters such as strength and elasticity of the native tissue vary interpersonally . FurtherThis review was based on a compilation of selected studies concerning mesh and biomaterials innovations using Pubmed, Embase and Web of Science databases. It is important to emphasize the lack of good quality clinical studies and the great difficult to compare them due to different methodologies. Moreover, the majority of studies are experimental and current literature does not have a reliable animal model for stress urinary incontinence and/or prolapse repair. Although it has already been tested by numerous previous experiments to evaluate graft and prosthesis integration, the rat subcutaneous tissue surely is not the ideal experimental model. In current literature different models have been tested with interesting findings, including rabbit and sheep's vagina models , 41. ThuThe major controversy is still the use of meshes for pelvic organ prolapse repair. The literature does not have strong evidences, which support their use for that purpose as a routine. Therefore, continuous research is needed in order to find an ideal biomaterial, with an adequate size, weight and features for lowering the risk of infection and integration defects. Moreover, as concluded by Barski et al. in a meta-analysis, careful individualized selection of patients and materials, education of patients, and elimination of identified risk factors are urgent prior to implantation of vaginal meshes .The vagina is considered a clean-contaminated field. Mesh complications, such as erosion, may be linked to bacterial contamination at the time of mesh insertion . The proRecently, many combinations of composite meshes have been tested  but with conflicting results. It is important to state that some evidences are based on experimental studies without an adequate control, and with a short follow-up . MoreoveConcerning the ideal mesh weight, light or ultralight meshes tend to become first choice, because of its better biocompatibility, but still needs further improvements to avoid the risk of higher recurrence rate.Coating agents seems to be a great potential strategy, highlighting antibiotic and corticosteroid coating with interesting preliminary in vitro results. Silver and titanium's use should have its cytotoxicity and biomechanical aspects clarified.Due to its availability, biocompatibility, low immunogenicity and favorable biological properties , collageCell-based technology will surely become one of the most relevant approaches for soft tissue disorders in a few years. However, so far, only limited evidence exists and, especially considering POP's treatment, cell-based tissue engineering is still just speculation.Biomaterials research have recently emerged worldwide as a result of an urgent need for more appropriate options for reconstructive medicine and treatment of soft tissue disorders. Composite or coated meshes intending to get antiadhesive profile, protection against infection or to elicit less pronounced foreign body reaction have been tested. Although significative basic science information has been produced, there are still conflicting results. Also, tissue-engineering techniques have shown only limited evidence till now. As the life expectancy is growing quickly, efforts in biomaterials research must be reached, in order to offer long lasting therapeutic options for re-constructive surgery.


Insects communicating with pheromones, be it sex- or aggregation pheromones, are confronted with an olfactory environment rich in a diversity of volatile organic compounds of which plants are the main releaser. Certain of these volatiles can represent behaviorally relevant information, such as indications about host- or non-host plants; others will provide essentially a rich odor background out of which the behaviorally relevant information needs to be extracted. In an attempt to disentangle mechanisms of pheromone communication in a rich olfactory environment, which might underlie interactions between intraspecific signals and a background, we will summarize recent literature on pheromone/plant volatile interactions. Starting from molecular mechanisms, describing the peripheral detection and central nervous integration of pheromone-plant volatile mixtures, we will end with behavioral output in response to such mixtures and its plasticity. Insects often use pheromones to communicate intraspecifically and resource-related volatiles to forage or localize hosts. These two functional classes of semiochemicals are generally involved in different types of behaviors for instance sexual or social for pheromones and feeding or reproductive behaviors for plant volatiles but may interact with each other. Pheromones in general and more specifically sex pheromones are mostly blends of a few components emitted in a species-specific ratio. In moths, which will be in the focus of the present review, males have a highly sophisticated detection system to recognize very small amounts of the female-emitted sex pheromone and orient towards a small source based on spatio-temporal distribution of pheromone filaments . On the One of the major questions arising due to the co-existence of these two functional odor classes is whether interactions occur between pheromones and plant volatiles in the insect’s perceptual and processing system. Due to their different temporal occurrence in nature, we further discuss if a specific long-lasting background of plant odors, such as for example host plant cues, might facilitate orientation of a male moth following a female sex pheromone plume in which it encounters pulses of the species-specific sex pheromone. Indeed in several species, females release their pheromone from specific host plants and the host volatile emissions stimulate pheromone emission (reviewed in ). On theIn this article we review the literature on pheromone-plant odor interactions at different integration levels from signal reception up to protocerebral integration, with an emphasis on mechanistic aspects. We then analyze the plasticity of such interactions as a function of intrinsic and extrinsic factors and describe what is known on the orientation behavior towards mixtures of pheromone and plant odors. Finally, we briefly discuss what is known about consequences of pheromone-plant odor interactions at an evolutionary scale.i.e., the lateral protocerebrum and the mushroom bodies )D. melanogaster indicate that information collected by third order neurons in the lateral protocerebrum is still segregated as a function of corresponding glomeruli within the AL, whereas Kenyon cells, third order neurons within the mushroom bodies, seem to integrate a wide range of odorants across glomeruli [Manduca sexta, different projection areas in the lateral protocerebrum have been described even earlier [Data obtained in the fruit fly lomeruli ,64. In t earlier  for AL n earlier . On the  earlier . Also in earlier . These fBombyx mori, a species that shows orientation behavior to the major pheromone component, bombykol, alone, protocerebral neurons responded to bombykol as a single stimulus  [C. pomonella. Both males and females pre-exposed to the sex pheromone respond better behaviorally to the kairomonal attractant pear ester [S. littoralis males reared on a specific host plant as larvae, are, once adults, more attracted to the female sex pheromone in combination with volatiles from the experienced host plant when compared to pheromone and volatiles from a host plant they had not experienced [Evidence has accumulated that experience with a sensory stimulus can modulate subsequent responses not only to the same but also to other sensory signals. In this case we can postulate some “delayed interaction” between different sensory signals. Experience with either the sex pheromone or plant odors might modify responses to the other stimulus at a later moment in time. The most striking example is an increased behavioral response to the sex pheromone in r sound) ,74. Thisr sound) ,74. Thesr sound) . A similar ester . Also, oerienced .Pheromone perception triggers a sustained upwind flight in male moths (positive anemotaxis). In order to follow an intermittent pheromone plume in a turbulent environment, males alternate phases of upwind surge when perceiving pheromone filaments and lateral casting when loosing them (summarized in ). BesideThe influence of host plant odors on pheromone-triggered behavior has been studied either under field conditions by comparing the attractiveness of mixed pheromone plant-odor lures to pure pheromone lures, or in a wind tunnel by analyzing the flight behavior of male moths. Under field conditions, adding some of the compounds identified in the volatile emissions of adult or larval food plants to the sex pheromone led to increased catches in pheromone traps in several moth species -β-farnesene, linalool, or (Z)-3-hexenol in a wind tunnel [Grapholita molesta [Lobesia botrana, host plant volatiles added to a sub-optimal pheromone dose  were also shown to increase the proportions of take off and source contacts up to the response levels of the optimal pheromone dose alone [Eupoecilia ambiguella revealed that males were activated sooner and reached the source faster in presence of mixed stimuli [Besides those field studies that consider only the scores of male catches, but cannot evidence changes in their navigational behavior, dedicated wind tunnel studies are necessary to understand the mechanisms by which plant odor and pheromone information are integrated. Attraction of male codling moths, d tunnel . In cont molesta . A five-se alone . Interes stimuli . InteresS. littoralis walking in a locomotion compensator [Besides these direct effects of the odor environment, insects are expected to encounter very different odorant backgrounds during their flight toward a pheromone source. Sudden changes in background temporarily alter the orientation behavior of male pensator  , the searching sex is found to respond more to a mixture of pheromone and plant compounds, compared to the pheromone alone. This phenomenon can be linked to habitat localization, during which an insect uses general cue characteristics of the habitat of its host (herbivore or parasite) or prey (predator) to locate the host habitat, and subsequently relies on more specific cues to finally find its host or prey inside the habitat. In oligophagous species, the probability of finding a mate on the host plant is especially high since host plant odors can stimulate pheromone emission  and is moths ). In lesis moths . In extr females .Aggregation pheromones may be produced by one sex only but attract both sexes. The resulting aggregation behavior unites males and females ready to mate, and apart from serving reproduction, is often associated with feeding on a host plant. In these cases, reproduction and feeding behaviors are intimately associated, and pheromone and plant odors are involved at the same time and place so that their interactions contribute equally to reproduction and host exploitation. Palm weevils for example mate on palm trees on which adults also feed, and partner finding is mediated by a male-emitted pheromone and short chain products of fermentation released by the host tree ,96,97. IDysaphis plantaginea, emit a 1:8 blend of nepetalactolone and nepatalactol that attracts males. These compounds are shared with several other aphid species and the ratio is not sufficient to guarantee species specificity in mate location. Female aphid infestation induces increased release of four esters from the host leaves. Combination of these esters applied in a 1:1:1 ratio with the pheromone blend increases the number of D. plantaginea but decreased the number of other aphids caught in traps [Zeiraphera diniana feed either on larch or on cembran pine. Pheromone composition differs significantly between the two host races but cross-attraction can occur at a rate of 0.03–0.38. Cross attraction to larch females increases when they call from neighborhoods rich in pine or on pine trees. Cross-attraction to pine females similarly increases when calling from neighborhoods rich in larch. The plant environment thus affects assortative attraction to pheromone [In most moths, the chemical composition of the pheromone blends guarantees the species-specificity of attraction; it is the main factor contributing to the reproductive isolation, and the host plant is not necessarily required for mate finding. However, some examples are known in Aphids  and tortin traps . Host raheromone ,106,107.The research summarized in this review shows that insects use their surrounding odor landscape in manifold ways when responding to pheromones. On the other hand, abundant volatiles can also mask crucial odors and challenge the chemical specificity of specialized receptors potentially imposing selective pressure on insects to develop neuronal mechanisms to extract relevant information from an odor background. The biological relevance of either outcome of interactions between pheromone and plant odor information is still under discussion and most likely depends on the insect species, the environmental context and the precise compounds involved.Pheromone-plant odor interactions might also play a role in the evolution of mating communication systems and their contribution to reproductive isolation. There are a few examples in the literature showing that the attraction specificity of reconstituted pheromone blends depends on the plant on which the traps have been settled . Host plSo far, most studies on odor interactions treat behavioral and neuronal responses during simultaneous stimulation, however, recent publications ,14 aim a


Plasmodium falciparum and Plasmodium vivax vaccine antigens. In this review, we describe how population genetic approaches can be applied to this rich data source to predict the alleles that best represent antigenic diversity, polymorphisms that contribute to it, and to identify key polymorphisms associated with antigenic escape. We also suggest an approach to summarize the known global diversity of a given antigen to predict antigenic diversity, how to select variants that best represent the strains circulating in natural parasite populations and how to investigate the strain-specific efficacy of vaccine trials. Use of these strategies in the design and monitoring of vaccine trials will not only shed light on the contribution of genetic diversity to the antigenic diversity of malaria, but will also maximize the potential of future malaria vaccine candidates.After more than 50 years of intensive research and development, only one malaria vaccine candidate, “RTS,S,” has progressed to Phase 3 clinical trials. Despite only partial efficacy, this candidate is now forecast to become the first licensed malaria vaccine. Hence, more efficacious second-generation malaria vaccines that can significantly reduce transmission are urgently needed. This review will focus on a major obstacle hindering development of effective malaria vaccines: parasite antigenic diversity. Despite extensive genetic diversity in leading candidate antigens, vaccines have been and continue to be formulated using recombinant antigens representing only one or two strains. These vaccine strains represent only a small fraction of the diversity circulating in natural parasite populations, leading to escape of non-vaccine strains and challenging investigators’ abilities to measure strain-specific efficacy in vaccine trials. Novel strategies are needed to overcome antigenic diversity in order for vaccine development to succeed. Many studies have now cataloged the global diversity of leading  Plasmodium and is transmitted by female anophelene mosquitoes. Of the 3.4 billion people in 108 countries at risk of malaria, 1.2 billion are at high risk of disease. In 2012, it was estimated that this disease caused 2000 deaths per day, the majority (77%) being children <5 years of age in sub-Saharan Africa infected with Plasmodium falciparum, the most virulent of the five known human malaria parasites .Haplotype: a combination of alleles in a gene or gene region carried by a particular parasite clone.Serotype: a haplotype from a gene or gene region that is antigenically unique and induces strain-specific responses.Monovalent vaccine: a vaccine containing only one distinct antigen or one allele of the same antigen.Multivalent vaccine: a vaccine containing two or more distinct antigens, or two or more alleles of the same antigen.A long lasting, broadly efficacious malaria vaccine would be the most sustainable approach to control and eventually eradicate malaria. That a malaria vaccine may be feasible is strongly supported by the fact that people living in malaria endemic areas develop protective immunity against malaria symptoms during childhood . By adulDespite numerous promising malaria vaccine candidates and several partially successful malaria vaccine trials –25, shorBy 2015, develop and license a first generation malaria vaccine that has a protective efficacy of more than 50% against severe disease and death and lasts more than one year .In the last decade, there has been an attempt to assist and accelerate development of a malaria vaccine with the establishment of the PATH Malaria Vaccine Initiative (MVI), which has greatly progressed the evaluation and identification of promising malaria vaccine candidates. To further focus and unite the global vaccine effort, in 2006 the World Health Organization (WHO) launched the first malaria vaccine technology roadmap with the landmark goal:Currently, a single vaccine candidate is on track to meet this goal. Known as “RTS,S,” this vaccine is based on the repeat region and T-cell epitopes of CSP. RTS,S is the subject of a large multicentre Phase 3 trial involving more than 15,000 children over 11 sites in sub-Saharan Africa. The full results of the trial have not yet been published; however, after three doses, clinical malaria cases during the first 18 months of follow-up decreased by an estimated 46% (severe disease by 36%) in children 5–17 months of age at first vaccination, and 27% (severe disease by 15%) in infants aged 6–12 weeks of age at first vaccination , therefoP. falciparum and P. vivax that encompass: (i) development of second-generation malaria vaccines that provide a protective efficacy of more than 75% against clinical (mild and severe) malaria … and (ii) development of malaria vaccines that reduce transmission of the parasite and thereby reduce the incidence of human infection …  ((i)pre-erythrocytic vaccines: these vaccines aim to prevent infection by targeting the infective stage, known as the sporozoite . Alternatively, pre-erythrocytic vaccines can target antigens expressed by liver stage parasites to prevent the emergence of merozoites into the bloodstream, the stage of infection responsible for the clinical symptoms of malaria infection blood stage vaccines: the vast majority of malaria vaccine candidates are designed to protect against the blood stage of infection . PfEMP1 mediates adhesion to host cells, a mechanism that is associated with severe malaria .Determining the extent and distribution of immunologically relevant diversity for potential malaria vaccine candidates will help to determine the feasibility of whether a regionally or globally effective vaccine can be developed for the particular target. It is therefore important to focus the analysis to only those polymorphisms with the greatest likelihood of creating antigenic diversity to allow immune escape. Once polymorphisms predicted to be under balancing selection have been identified , and parasite density. However, only a few malaria vaccine trials have determined whether efficacy against vaccine or closely related strains has been achieved , 92, 131The low prevalence of vaccine alleles within natural populations has been proposed to limit vaccine efficacy , 138. Fu(i)measuring strain-specific protection by assessing risk of clinical episode associated with parasites carrying the vaccine-allele compared to those carrying any non-vaccine allele;(ii)measuring cross-strain protection by assessing risk of clinical infection with parasites carrying the vaccine-allele compared to those carrying different non-vaccine alleles;(iii)measuring vaccine-mediated selection by:comparison of allele or haplotype frequencies before and after vaccination in the different vaccine groups;comparison of the incidence of infection with parasites carrying different haplotypes and individual polymorphisms before and after vaccination;(iv)assessment of vaccine-mediated strain-specific natural immunity by measuring antibodies to vaccine alleles in vaccine and control groups.In addition to measuring strain-specific endpoints by determining the time to first clinical episode with vaccine and non-vaccine alleles, the analysis of outcomes in control and vaccine groups provide an opportunity for more detailed analyses that can provide key insights into the complexities of parasite antigenic diversity , 153. InThe development and licensing of an effective malaria vaccine will require sustained and intensive surveillance to monitor for vaccine-mediated selection of non-vaccine alleles and to ensure that vaccine alleles are common enough for vaccines to remain effective. Regular population genetic surveys will be required in order to monitor allele frequencies, to ensure that alleles contained within the vaccine continue to represent the diversity of the parasite population and that new, potential antigenic escape mutants have not emerged. A genetic surveillance system would be difficult and costly to implement, but the development of low cost rapid assays to quickly genotype parasite isolates would facilitate such an approach . The neeThe trials and tribulations of malaria vaccine development have reached a critical juncture. The first licensed malaria vaccine is almost at hand and children in African countries stand to benefit greatly from its availability. However, this vaccine is only partially effective against the symptoms of malaria, not infection, and provides only short-lived protection . As a reAlyssa E. Barry and Alicia Arnott wrote the paper, collated data, and prepared figures.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.


Compared to univariate analysis of genome-wide association (GWA) studies, machine learning–based models have been shown to provide improved means of learning such multilocus panels of genetic variants and their interactions that are most predictive of complex phenotypic traits. Many applications of predictive modeling rely on effective variable selection, often implemented through model regularization, which penalizes the model complexity and enables predictions in individuals outside of the training dataset. However, the different regularization approaches may also lead to considerable differences, especially in the number of genetic variants needed for maximal predictive accuracy, as illustrated here in examples from both disease classification and quantitative trait prediction. We also highlight the potential pitfalls of the regularized machine learning models, related to issues such as model overfitting to the training data, which may lead to over-optimistic prediction results, as well as identifiability of the predictive variants, which is important in many medical applications. While genetic risk prediction for human diseases is used as a motivating use case, we argue that these models are also widely applicable in nonhuman applications, such as animal and plant breeding, where accurate genotype-to-phenotype modeling is needed. Finally, we discuss some key future advances, open questions and challenges in this developing field, when moving toward low-frequency variants and cross-phenotype interactions.hidden heritability component that has remained missing because of too small marginal effects to pass the stringent genome-wide significance filters Supervised machine learning aims at constructing a genotype–phenotype model by learning such genetic patterns from a labeled set of training examples that will also provide accurate phenotypic predictions in new cases with similar genetic background. Such predictive models are increasingly being applied to the mining of panels of genetic variants, environmental, or other nongenetic factors in the prediction of various complex traits and disease phenotypes regularized machine learning models, which enforces constraints on the complexity of the learned models so that they would ignore irrelevant patterns in the training examples. Simple risk allele counting or other multilocus risk models that do not incorporate any model parameters to be learned are outside the scope of this review; in fact, such simplistic models that assume independent variants may lead to suboptimal prediction performance in the presence of either direct or indirect interactions through epistasis effects or linkage disequilibrium, respectively model overfitting, i.e., models not being capable of generalizing to new samples two-stage approachesWe argue here that many medical applications of machine learning models in genetic disease risk prediction rely essentially on two factors: effective model regularization and rigorous model validation. We demonstrate the effects of these factors using representative examples from the literature as well as illustrative case examples. This review is not meant to be a comprehensive survey of all predictive modeling approaches, but we focus on The aim of risk models is to capture in a mathematical form the patterns in the genetic and non-genetic data most important for the prediction of disease susceptibility. The first step in model building involves choosing the functional form of the model , and then making use of a given training data to determine the adjustable parameters of the model . While it is often sufficient for a statistical model to enable high enough explanatory power in the discovery material, without being overly complicated, a predictive model is also required to generalize to unseen cases.One consideration in the model construction is how to encode the genotypic measurements using genotype models, such as the dominant, recessive, multiplicative, or additive model, each implying different assumptions about the genetic effects in the data iy to be predicted for an individual i is modeled as a linear combination of the individual's predictor variables ijx:jw are assumed constant across the n individuals, w0 is the bias offset term and p indicates the number of predictors discovered in the training data. In its basic form, y (linear regression). For case-control classification, the binary dependent variable y is often transformed using a logistic loss function, which models the probability of a case class given a genotype profile and other risk factor covariates x (logistic regression). It has been shown that the logistic regression and naïve Bayes risk models are mathematically very closely related in the context of genetic risk prediction Statistical or machine learning models identify statistical or predictive interactions, respectively, rather than biological interactions between or within variants Model regularization refers to the technique of controlling the model complexity, with the aim of preventing overfitting the model to the training data, and hence to improve its generalization capability to new samples. Classical regularization approaches rely on explicit penalization of the model complexity through penalty terms such as L1 and L2 norms for model weights  algorithm In addition to the classical regularization approaches, where an explicit model complexity penalization term is included in the optimization problem , alternamultivariate filters have also been proposed, including the Relief family of approaches Whereas classical, univariate filter methods evaluate the relevance of each genetic feature independently of the others, more advanced population stratification, leading to either false positives or false negative detections. To avoid the need to cluster the data into smaller substrata according to population structures, learning machines can be complemented by information of such substructures extracted using feature extraction methods, such as EIGENSTRAT, PCA, or MDS Even advanced machine learning methodologies have been shown to be negatively affected by the presence of Linkage disequilibrium (LD) tends to lead to the selection of highly correlated genetic features when using unpenalized modeling approaches whole-genome prediction (WGP) models fit all of the genotyped variants of the genetic data onto ridge regression type of linear models, such as genomic best linear unbiased prediction (GBLUP) or its variants Finally, feature selection is commonly implemented to identify the subset of variants having most predictive power for the particular phenotypic trait. The aims of feature selection include the reduction of the dimensionality of the genetic search space, excluding correlated variants without independent contribution to the prediction, and facilitating the implementation of the final prediction model, for instance, in clinical setup. Three main types of feature selection methods have traditionally been considered in the context of genetic predictors: filters, wrappers, and embedded methods . While such standard models have provided relatively good predictive accuracies, as assessed using simulation studies or hypothetical effect size distributions A class of widely used filter approaches includes the standard multilocus genetic risk models, where the risk alleles and their weights are determined through single-locus statistical tests, such as odds–ratio, R2)  or as a regression formulation . Regardless of the problem formulation, however, the critical issue is how to guarantee that the model estimated in the training sample enables generalization power on new sets of individuals using appropriate learning models and regularization approaches. Another important issue is how to evaluate and quantify the predictive performance of these models using procedures such as cross validation (CV) and statistics such as the area under the curve (AUC) or coefficient of determination (R2) . These fL2-regularized (ridge) logistic regression enabled construction of a highly predictive risk model for type 1 diabetes (T1D) using less than 500 variants that passed a relatively stringent prefiltering threshold (p<10−5) on a case-control GWA dataset In one of the first machine learning applications, Wei et al. showed that support vector machines (SVM) and p<10−4), they preselected around 10,000 variants and applied regularized logistic regression with L1 penalty for sparse genetic risk modeling. In an independent validation set from the meta-analysis cohort, the predictive models achieved the best prediction performance reported for CD and UC  so far. In contrast, the simple odds–ratio-weighted genetic risk model showed relatively poor results . The study also confirmed the projections from previous works Recently, Wei et al. made use of larger sample sizes , using variant data from 15 European countries for risk prediction of Crohn's disease (CD) and ulcerative colitis (UC) R2 values were also confirmed in another study R2 values dropped dramatically when the fitted model was applied to an independent validation dataset using 10-fold CV  The final example comes from the regression formulation. With the aim to explain a part of the missing heritability of height, Yang et al. L2-regularized logistic (ridge) regression required a very large number of features, while showing reduced accuracy at a lower number of variants. Surprisingly, the popular L1-penalized logistic model showed slightly suboptimal performance; although its peak performance was similar to that of greedy RLS, it required a much larger number of variants in these datasets. We note that the relative behavior of these methods may well change in other genetic datasets and applications. In line with the previous results in CD and UC cases To illustrate the similarities and differences in their behavior, we ran a number of common regularization approaches on two example datasets . In bothL2-logistic and greedy RLS were from the major histocompatibility complex (MHC) region , in line with the previous studies The relatively small overlap in the selected features highlights an interesting point that the models tend to select different panels of variants while achieving rather similar prediction performance , suggestWhile rare variants have been proposed as one explanation for the missing heritability It has been argued that, even with increasingly large-scale and dense genomic data, genetic prediction alone may still not reach the accuracy regarded as clinically informative for the population at large An interesting question under debate is how many genetic features should be incorporated into the prediction models We envision a number of future directions for improvements in disease risk prediction. One exciting development involves modeling of cross-phenotype interactions (pleiotropy). Many genetic variants are associated with multiple disease phenotypes, particularly across autoimmune diseases, cancers, and neuropsychiatric disorders The current evidence contradicts the idea of a universally optimal model across datasets and prediction applications; rather, the model should be selected based on whether one is trying to achieve a maximally predictive model without restricting the number or type of variants, or whether the goal is to build a sufficiently predictive model with a limited number of genetic and nongenetic features. This highlights the importance of feature selection as a key component in the construction of prediction models, whether it is done explicitly in the optimization process  or implicitly through the model regularization (embedded models). One common finding is that those variants not meeting the stringent genome-wide significance levels may also contribute to the predictive signals when combined in the multilocus prediction modes Regardless of the model used, however, careful evaluation of its generalizability is critical for prediction applications. We encourage using systematic and unbiased procedures, such as nested CV, for the selection of genetic variables and other model parameters and for the evaluation of the generalization performance of the model. The final model construction and feature selection should be performed on the complete set of samples using standard CV options. However, the eventual predictive power must be assessed by implementing the final model on a sufficiently large, representative, and independent test set in order to avoid reporting over-optimistic prediction results. The model evaluation also depends on the application case; for instance, if the aim is to carry out disease screening in Finland, then a relatively large Finnish population sample should be used both in the model construction and validation.Genetic risk prediction through supervised machine learning models goes beyond the single-locus association testing with the complex disease phenotypes. The main objective of regularized learning approaches is to find the most predictive combinations of variants, the functional roles of which must to be validated using follow-up experimentation. However, it is likely that predictive power is linked to the underlying biological mechanisms and even causality, but whether this comes through the selected variants and their interactions, or via synthetic associations or other nondirect relationships needs to be evaluated mechanistically. Genotype–phenotype modeling is a highly challenging problem, but we believe that through appropriate implementation and application of the supervised machine learning methods, such as those presented here, increasingly predictive relationships and biological understanding will be extracted from the current and emerging genetic and phenotypic datasets.Text S1Implementation details for a range of regularized machine learning models.(PDF)Click here for additional data file.


Depression is a debilitating mental health condition that often requires treatment with antidepressant medication. Although this approach is usually effective in managing clinically diagnosed depression, depression that is comorbid with diabetes responds poorly to currently available antidepressants. This has fuelled the idea that the underlying pathophysiology of diabetes-associated depression might be fundamentally different, emphasising the need for increased research efforts in this area. In this study, Guyu Ho and co-authors demonstrate that an established mouse model of diabetes displays anxiety- and depression-like behaviours, supporting the comorbidity of depression and diabetes. By applying immunohistochemical and biochemical approaches in areas of the brain that are known to govern mood control, they provide evidence that neural cell death occurs in association with the depressive phenotype of diabetic mice. Furthermore, they show that hyperglycaemia-induced mitochondrial dysfunction could play a role in driving apoptosis in brain cells. These findings suggest that, in contrast with standalone depression, neural cell death could contribute to depression that occurs with diabetes. This could have implications for the development of new neural-protective therapies to treat depression in individuals with diabetes.


A collaborative approach to patient management has been shown to improve patient outcomes. In a resource-limited NHS, critical care beds are at a premium, therefore preventing unnecessary admissions by optimising ward-based management is essential. The objective of this service quality improvement project was to improve collaboration between the critical care directorate and neurosurgical high care unit at a tertiary university teaching hospital. We proposed that the use of a simple ward round tool on collaborative rounds would facilitate systematic patient review, prompt early recognition of those critically unwell and improve patient outcomes.An initial observation period of behaviours and practice on the neurosurgical unit was conducted with qualitative and quantitative data collection. Following analysis of these outcome measures a simple ward round tool was constructed, with the mnemonic ‘DON'T FORGET', and we devised a programme for collaborative ward rounds to take place three times per week over a 1-month period. During this time further data were collected to assess whether our interventions resulted in modified behaviours and to document the number of changes made to patient management as a consequence of the collaborative approach to care.Our results showed that improvements were made in all assessed domains. Consultant-led ward rounds increased, attendance by members of the multidisciplinary team (MDT) dramatically improved and as a result MDT discussion was enhanced. In addition, documentation of structured plans improved and review of prescription charts significantly increased. As a consequence of collaborative rounds, a total of 343 changes were made to patient management under the domains of the ward round tool. This was an average of 21.4 changes per collaborative round, with most changes being made to medication charts or decisions regarding thromboprophylaxis.The use of a simple ward round tool combined with a collaborative approach to ward rounds improved MDT involvement and discussion, promoted structured patient review and resulted in positive changes to multiple areas of patient management. In conclusion, structured collaborative rounds result in significant changes to patient management that may prevent admission, or readmission, to critical care which has the potential to reduce healthcare costs and morbidity.


Oxidative phosphorylation (OXPHOS) is the primary source of ATP in eukaryotes and serves as a mechanistic link between variation in genotypes and energetic phenotypes. While several physiological and anatomical factors may lead to increased aerobic capacity, variation in OXPHOS proteins may influence OXPHOS efficiency and facilitate adaptation in organisms with varied energy demands. Although there is evidence that natural selection acts on OXPHOS genes, the focus has been on detection of directional (positive) selection on specific phylogenetic branches where traits that increase energetic demands appear to have evolved. We examined patterns of selection in a broader evolutionary context, i.e., on multiple lineages of fishes with extreme high and low aerobic performance.We found that patterns of natural selection on mitochondrial OXPHOS genes are complex among fishes with different swimming performance. Positive selection is not consistently associated with high performance taxa and appears to be strongest on lineages containing low performance taxa. In contrast, within high performance lineages, purifying (negative) selection appears to predominate.We provide evidence that selection on OXPHOS varies in both form and intensity within and among lineages through evolutionary time. These results provide evidence for fluctuating selection on OXPHOS associated with divergence in aerobic performance. However, in contrast to previous studies, positive selection was strongest on low performance taxa suggesting that adaptation of OXPHOS involves many factors beyond enhancing ATP production in high performance taxa. The broader pattern indicates a complex interplay between organismal adaptations, ATP demand, and OXPHOS function.The online version of this article (doi:10.1186/s12862-015-0453-7) contains supplementary material, which is available to authorized users. Physiological processes may serve as mechanistic links between genotypes and organismal phenotypes. Accordingly, adaptations in genes of energy metabolism pathways may facilitate the evolution of organismal structures and life habits with diverse energy requirements. Proteins encoded by the mitochondrial genome serve as core subunits of the oxidative phosphorylation (OXPHOS) system, the primary source of ATP in eukaryotic cells. Consequently, organismal traits with differing ATP demands may be influenced by adaptation in mitochondrial genomes –5. Our uEvidence of positive selection on OXPHOS genes has been associated with evolution of a variety of energetically demanding characteristics (reviewed in ), includOXPHOS functional efficiency may be particularly important to energy intensive processes such as locomotion. Variation in locomotive performance of fishes is among the most extreme among vertebrates, ranging from largely sedentary filter feeders and sit-and-wait predators to highly migratory species and active pelagic foragers. For example, seahorses and flounders spend much of their time nearly motionless, while tunas and marlins are “high-performance” swimmers that exhibit high aerobic metabolism and prolonged fast swimming , 21. HigAt the molecular level, expression levels of proteins directly involved in energy metabolism may be increased in highly mobile fish species. Tunas and marlins, which have higher cruising speeds than other active fishes , have be+/2e ratio) (reviewed in ).We examined evidence for adaptation of mitochondrial OXPHOS genes in fishes with different swimming performance. Selection was investigated for specific amino acids sites across the whole phylogenetic tree for these species, as well as for amino acid sites on individual branches of the tree. The results show a strong signal of positive selection on branches in the ancestral parts of the tree, and branches leading to low- and moderate-performance swimmers. However, no evidence of positive selection was observed within clades of the high-performance tunas or billfishes. We did not observe a disproportionate effect of selection on any particular gene as all genes exhibited some positively selected sites but this varied across branches of the tree. We also show that many of the sites identified as being under positive selection occur in structural regions where they may have effects on OXPHOS function. Positively selected sites in other regions may also have functional significance, but their potential effects are less clear.Our results show the strongest signal of positive selection on branches leading to the lowest performance fishes, while purifying selection was identified on the branches of high performance fishes. This result is in strong contrast to previous studies that have exclusively examined the hypothesized association of positive selection on OXPHOS with increased energetic demands required by higher organismal performance (reviewed in ). Our reA common expectation is that positive selection should lead to enhanced organismal performance. Moreover, it might be expected that positive selection will lead to increased functional efficiency of OXPHOS in response to the increased ATP demands associated with enhanced performance. In the absence of information on the exact functional significance of individual substitutions, the effects of positive selection to increase or decrease OXPHOS efficiency in these taxa remains unknown. However, our results do not match simple expectations. Positive selection appears to be heterogeneous, fluctuating over phylogenetic time scales, with no simple relationship between the strength of selection and organismal performance. However, one clear pattern is that there is strong functional constraint (negative selection) in these high performance systems and directional selection on these lower performance groups.MT-CO1 [MT-CO2 [N in the lineage leading to hominids that appears to be associated with increased brain size. Grossman et al. [MT-CO4, a nuclear gene in OXPHOS complex IV in catarrhine ancestors of hominids in the period between 18 and 40 Mya and then decelerated in the descendant hominid lineages. On the lineage leading to bats, the only mammals capable of powered flight, eight OXPHOS genes were found to have undergone positive selection [Orcinus orca). In addition, the MT-ND2 and MT-ND5 genes of highly migratory Pacific salmon exhibit evidence of positive selection [Our results appear to contrast with previous studies where positive selection or evolutionary rate variation was found on lineages leading to organisms with high ATP demands. For example, MT-CO1  and MT-C [MT-CO2  exhibiten et al.  found acelection  found twelection .MT-CO2) on several branches among high-performance fishes, including billfishes and tunas. They found ω was not increased in lineages leading to the tunas but was significantly increased in the lineage preceding the billfish . However, the phylogeny used in [MT-CO1, 2, and 3) on the single lineage leading to billfishes and found positive selection along that lineage when flatfishes were excluded but no selection was detected when flatfishes were included. The latter result is consistent with our findings and as suggested by Little et al. [Our results are consistent with previous studies of the high-performance taxa examined here. Dalziel et al.  examined used in  does not used in  examinede et al.  emphasizWith respect to negative selection on high performance fishes, we speculate that once a reasonably efficient OXPHOS system evolved it may have become difficult to change in the high performance groups. The high performance system might be expected to have a much lower tolerance for non-synonymous substitutions as most (even slight) changes would be likely to have negative functional effects. Conversely, lower performance swimmers may have a much broader tolerance for non-synonymous substitutions because the OXPHOS system is under much lower performance demands. We envision the high performance swimmers as occupying a local optimum on a fitness landscape , but the+/2e ratio (increased slippage) due to altered protein structures could be adaptive in low performance species. OXPHOS regulation is highly complex and involves mechanisms independent of structural OXPHOS proteins. Elevated expression of OXPHOS genes and others involved in aerobic respiration could clearly increase aerobic capacity in the absence of selection on specific OXPHOS variants. However, it is clear that positive selection acts on OXPHOS proteins and the effects of positive selection are frequently associated with the evolution of differences in ATP demand.It is also possible that organismal fitness in taxa with low energy demands may be increased by a modified OXPHOS regulatory system or even a reduction in OXPHOS efficiency. In such cases, we would expect to see evidence of positive selection on OXPHOS genes in these taxa. Because there may be trade-offs between OXPHOS rate or efficiency and deleterious effects, reducing OXPHOS efficiency may be adaptive in systems where ATP demand is chronically low. For example, maintenance of a strong chemiosmotic gradient in organisms with low ATP demand may cause increased production of reactive oxygen species (ROS)  leading +/O ratio (how many protons do mitochondria pump from matrix into inter-membrane space for each oxygen atom consumed), and the H+/ATP ratio (how many protons flow back to the matrix for each ADP molecule phosphorylated to ATP) in these fish species.There are other issues that could affect the efficiency of ATP generation of OXPHOS in high-performance tunas and billfishes. Tunas and billfishes exhibit high metabolic rates to generate ATP to support their high swimming performance (thus high OXPHOS efficiency). However, they are among the few endothermic species of fishes , 79, 80 Drosophila, they provide strong evidence that OXPHOS variation affects organismal performance and fitness in the wild.High mitochondrial respiration capacity can be achieved through means other than modification of OXPHOS efficiency via genetic variation, such as increased mitochondrial density per tissue mass, more closely packed inner mitochondrial membrane cristae, increased metabolic enzyme activity, increased expression of genes involved in a number of different but related biological pathways such as glycolysis, the Krebs cycle, and fatty acid metabolism. In addition, swimming performance, as in our qualitatively defined groups, may have arisen due to many different morphological and physiological characteristics beyond OXPHOS function. We do not assert that all variation in swimming performance is due to OXPHOS variation, only that some unknown fraction of the performance variation is positively associated with natural selection. A number of recent studies have presented evidence for direct effects of OXPHOS variation on organismal fitness, many with an identified mechanistic basis –86. WhilIn conclusion, we found that patterns of natural selection on mitochondrial OXPHOS genes are complex among fishes with different swimming performance. The type and direction of selection are heterogeneous through evolutionary time and vary in ways that would not be readily predicted based solely on organismal performance. The most striking result was extensive positive selection on low-performance swimmers. Although examination of the most recent lineages indicates that positive selection is inversely proportional to organismal performance, the broader pattern indicates a complex interplay between organismal adaptations, ATP demand and OXPHOS function through evolutionary time.The data sets supporting the results of this article are included in its additional files.


The tenet that ecological opportunity drives adaptive diversification has been central to theories of speciation since Darwin, yet no widely accepted definition or mechanistic framework for the concept currently exists. We propose a definition for ecological opportunity that provides an explicit mechanism for its action. In our formulation, ecological opportunity refers to environmental conditions that both permit the persistence of a lineage within a community, as well as generate divergent natural selection within that lineage. Thus, ecological opportunity arises from two fundamental elements: (1) niche availability, the ability of a population with a phenotype previously absent from a community to persist within that community and (2) niche discordance, the diversifying selection generated by the adaptive mismatch between a population's niche-related traits and the newly encountered ecological conditions. Evolutionary response to ecological opportunity is primarily governed by (1) spatiotemporal structure of ecological opportunity, which influences dynamics of selection and development of reproductive isolation and (2) diversification potential, the biological properties of a lineage that determine its capacity to diversify. Diversification under ecological opportunity proceeds as an increase in niche breadth, development of intraspecific ecotypes, speciation, and additional cycles of diversification that may themselves be triggered by speciation. Extensive ecological opportunity may exist in depauperate communities, but it is unclear whether ecological opportunity abates in species-rich communities. Because ecological opportunity should generally increase during times of rapid and multifarious environmental change, human activities may currently be generating elevated ecological opportunity – but so far little work has directly addressed this topic. Our framework highlights the need for greater synthesis of community ecology and evolutionary biology, unifying the four major components of the concept of ecological opportunity. Despite the central place of the concept and its antecedents in historical Darwin  and currWhile we currently have no specific, widely accepted definition of “ecological opportunity,” common themes in its usage are evident. These themes pervade early exposition of the general concept by George G. Simpson and David Lack, who are often credited with the concept's inception. Simpson  wrote “T“the adaptive factor [in speciation] is adjustment to…differences in local ecological conditions,” as did Dobzhansky  zero net growth isoclines (ZNGIs) and impact vectors of mechanistic niche models , and may occur by a broadening of the selective surface (niche expansion) or disruptive selection within a population, or by divergent selection acting between spatially segregated subpopulations. Within a single community, niche discordance might occur, for example, when a competitor or predator invades or becomes extinct, a new resource enters the community, or the climate changes. If, however, environmental change within a community does not result in diversifying selection, but instead only results in an overall shift in the phenotypic optimum across the lineage, then this does not comprise niche discordance because selection does not favor increased phenotypic variance in this case and should thus not lead to phenotypic diversification. In the context of multiple communities, niche discordance occurs when a dispersing subpopulation colonizes a new community, and biotic or abiotic circumstances of the new community impose altered selection on niche-related traits, favoring niche expansion or a change in mean phenotype. In the terms of evolutionary landscapes, niche discordance reflects a shift in the individual selection surface such that new or broader regions of niche-trait space now experience high fitness. This scenario favors a broader occupation of the adaptive landscape by a lineage, either within a community, as populations diverge in a sympatric setting, or across communities, as allopatric populations diverge.The concept of ecological opportunity is fundamentally coupled with the concept of the ecological niche. This connection is rooted in Darwin's view of ecology's determinative role in the formation of species and is made explicit in Gause's axiom that a species may persist within a community only if it differs sufficiently in ecological traits from other species Hardin . It follecological opportunity is a prospective, lineage-specific characteristic of an environment that contains both niche availability, allowing a population to persist in the environment, and niche discordance, causing diversifying selection within the lineage.With this framework, we offer a precise, working definition of ecological opportunity: Our definition of ecological opportunity shares features with previous characterizations, especially with regard to niche availability, which is often a central element of the concept's antecedents Lack . Niche dWe suspect that understanding the relationships and interactions between niche availability and niche discordance in the wild will allow insights into ecological opportunity's role in generating biological diversity. However, we currently have little knowledge on this topic because no prior framework for ecological opportunity explicitly delineated the importance of these two elements. One might anticipate a negative correlation between niche availability and niche discordance, as a colonist population with high niche availability might typically already reside near a fitness peak and thus experience little niche discordance because the similar fitness surfaces across habitats impart little or no diversifying selection Fig.. MoreoveDiversification under the influence of ecological opportunity is expected to progress in a more or less generalized way that we frame as a series of four “stages” Fig.. In Box Ecological opportunity can facilitate diversification through four general “stages” Fig.. HoweverThe initial expectation for a lineage experiencing ecological opportunity is an increase in phenotypic variance in traits associated with niche expansion or divergence Novel resources Novel competitors Novel enemies Novel abiotic stressors Novel background environments More depauperate communities While further theoretical work is needed, ecological opportunity should generally increase following large, rapid, and multifarious environmental shifts – like the changes that commonly result from human activities. This suggests that the strong and widespread environmental impacts of humans on a diverse array of biotic and abiotic factors may not only precipitate earth's sixth mass extinction event  or temporal variation in selection . Moreover, HIREC can even affect diversification potential of populations, for example, by altering gene flow via translocation of organisms, resulting in genetic admixture (including hybridization) and altered responses to selection  inhabiting the isolated and solitary island of Cocos. Lack variances of traits in a population, level of gene flow between diverging subpopulations, pleiotropic effects, and effective population size  in a population experiencing ecological opportunity over some time interval is to consider S as the product of three probabilities, E,V, and I  and frogs (ear papillae) may have strengthened I. Although their identification and study presents conceptual and empirical challenges (Donoghue E,V, or I appear associated with many radiations, and may underlie the most dramatic radiations in the history of life.Historical discussion of ecological opportunity and adaptive radiation has often considered “key innovations,” traits that permit taxa to interact with the environment in novel ways and lead to increased rates of diversification Losos . Key innDonoghue , novel tOn the Origin of Species, yet we have lacked a comprehensive framework for elucidating its scope, action, and consequences. Our goal has been to provide greater clarity to the concept of ecological opportunity by defining its fundamental elements, and we hope this exposition motivates more focused theoretical and empirical development. Much work remains. A central obstacle to a deeper understanding of the role of ecological opportunity in shaping the diversity of life is development of predictive approaches to its action. Despite the substantial conceptual importance of ecological opportunity, apparent from the concept's longstanding utility in evolutionary biology, it has so far lacked a predictive framework (Losos individually in various ways (e.g., Kisel and Barraclough Ecological opportunity has formed the core of our ideas for the evolution and buildup of biological diversity since Darwin's description of the basic concept in rk Losos . Such a Ecological opportunity lies at the intersection of community ecology and evolutionary biology, and advances in our understanding of adaptive diversification will benefit most from explicit synthesis of these disciplines. Are niche availability and niche discordance often positively or negatively associated in nature, and what conditions influence these associations? We need to understand how properties of ecological opportunity, its spatiotemporal structure, and diversification potential impact the scale of diversification. Do especially extensive or rapid radiations arise primarily from markedly high levels of ecological opportunity, or favorable spatiotemporal structure, or is elevated diversification potential most important? We need to elucidate broad patterns in the distribution, action, and magnitude of ecological opportunity. Of particular interest in this regard is determination of ways that ecological opportunity may differ quantitatively or qualitatively between depauperate and species-rich communities. Answers to this question will shed light on whether communities become saturated, or whether ecological opportunity is not limited by current diversity, or may in fact accelerate with increased diversity (Losos and Mahler


Multiple psychosocial factors appear to affect cancer progression in various populations; however, research investigating the relationship between psychosocial factors and outcomes following hematopoietic stem cell transplantation (HCT) is scarce. Subject to adverse immunological and psychological conditions, HCT patients may be especially vulnerable to psychosomatic health sequelae; therefore, we studied whether optimism and anxiety influence the pertinent clinical outcome of days to neutrophil engraftment (DTE).54 adults undergoing either autologous or allogeneic HCT completed self-report questionnaires measuring optimism and anxiety. We assessed the association between these psychosocial variables and DTE.Greater optimism and less anxiety were associated with the favorable outcome of fewer DTE in autologous HCT recipients, though this relationship was no longer significant when reducing the sample size to only subjects who filled out their baseline survey by the time of engraftment.Our findings are suggestive that optimism and anxiety may be associated with time to neutrophil recovery in autologous, but not allogeneic, adult HCT recipients. Further investigation in larger, more homogeneous subjects with consistent baseline sampling is warranted. Psychosocial factors affect cancer progression in multiple populations HCTs are associated with unique immunological and psychological conditions. Patients receiving transplants are more immunosuppressed than other cancer patients secondary to ablation of their native marrow. Furthermore, the clinical course of HCT may be more distressing than other cancer treatments, with potentially prolonged periods of physical and emotional isolation depending on the type of transplant, institutional practice, and potential complications Positive psychosocial variables such as optimism predict not only emotional, but also physical well-being after HCT, including survival Neutropenia is a major contributor to morbidity following transplant We investigated the association of optimism and anxiety with time to neutrophil recovery in a population of adult HCT recipients undergoing either autologous or allogeneic transplant. We hypothesized that greater optimism and less anxiety around the time of transplant would be associated with less time to neutrophil recovery.+ cells infused/kg of recipient body weight were controlled for. Allogeneic and autologous transplants were evaluated separately. All participants received homogeneous granulocyte colony stimulating factor (GCSF); therefore, it was not necessary to include GCSF as a covariate. Due to the small number of minorities, race was dichotomized as Caucasian or non-Caucasian.Patients entered the study between Day −20 and Day +3, with Day 0 being the day of stem cell transplant. The goal was to enroll participants as close to Day −8 as possible, but preferably at least prior to transplant. Most commonly, enrollment occurred at the last pre-transplant outpatient visit prior to transplant. Reasons for variation in enrollment time included lack of access to the patient at their pre-transplant visit due to patient, provider, or study staff conflicts or overlap. If a patient was unable to be approached at a pre-transplant visit, they were approached as soon as possible following hospital admission for transplant. On occasion this resulted in enrolling participants after their transplant if admission occurred on a Friday and the conditioning period was short, as occurs with multiple myeloma . One hundred and twenty-two patients were approached by a member of the research team for study participation; 64 (52%) agreed to participate and 54 provided complete psychosocial data. Any patient admitted to the Bone Marrow Transplant Program at the University of Rochester Medical Center for transplantation of any type, age ≥18 years of age or older and able to give informed consent and complete the study questionnaires was eligible to participate. There were no medical condition exclusions. Factors noted to affect neutrophil recovery rates including age, race, gender, conditioning regimen (myeloablative/non-myeloablative), stem cell source , and number of CD34Upon obtaining written informed consent (as close to Day −8 as possible), a member of the research team provided participants with the self-administered surveys and was available as long as necessary to answer any questions and ensure participants understood how to complete them. Participants were asked to complete the surveys independently to avoid any possible influence from the research staff. They were also asked to complete them as soon as possible to be picked up the following day by a research team member. There was variation in the time of survey completion, ranging from Day −20 to Day +32. Fifty-seven percent of subjects completed the surveys prior to transplant, 82% by Day +3, and 85% by Day +14.These variations were due to either or both a) variation in time of study enrollment or b) a delay in participants filling out the survey on their own and returning it. Reasons for delays in enrollment are noted as above. The psychological parameters assessed were:The Life Orientation Test (LOT) assesses individual differences in generalized optimism versus pessimism. The 10-item revised version (LOT-R) The 20-item State-Trait Anxiety Inventory, Trait Version (STAI-T) These psychosocial measures were utilized as part of a music therapy intervention study in which 32 participants were randomized to the music therapy intervention and 32 randomized to an expressive reading arm; both groups received the same time and attention support. Other psychosocial measures evaluated as part of the initial study included coping style, social support, locus of control, and religiousness. We chose to evaluate optimism and anxiety due to their availability and evidence in the literature to support their relationship with transplant outcomes.3 for ≥3 consecutive days, a clinically meaningful endpoint at which time the risk for serious bacterial or fungal infections starts to decrease DTE was measured as the day post-transplant that the absolute neutrophil count (ANC) was >500/mm+ cells. T-tests assessed the differences for autologous and allogeneic transplants in optimism and anxiety overall as well as for those who filled out their survey by Day +3 and those who did not. Analyses were additionally run for only those participants who filled out their survey by Day +3, effectively reducing any bias that knowledge of engraftment status might have on perceived anxiety or optimism. All analyses were carried out using SAS/STAT software, Version 9.3 of the SAS System  on a Windows 7 platform.Data are expressed as means ± SD for continuous variables and as the number (percentage) for categorical variables. DTE also included the range for each transplant type. Comparisons of patient characteristics for the transplant types were 2-sided and included the use of t-tests, chi-square, or Fisher's exact test, as appropriate to the data. P values of <.05 were considered to be statistically significant. Multiple regression analyses were conducted using a general linear model program. The analyses were carried out separately for autologous and allogeneic transplants. The outcome DTE was analyzed by optimism and anxiety separately while controlling both demographic and clinical covariates of age, race, gender, conditioning regimen, stem cell source, and number of CD34Patients' pre-transplant diagnoses included lymphomas , leukemias , solid tumors , multiple myeloma , and other hematologic disorders . Greater optimism and less anxiety were significantly associated with fewer DTE among autologous HCT recipients; however, these psychosocial factors were not significantly associated with DTE when evaluating the more restricted sample of participants who filled out their surveys by Day +3 . There wWe partially confirmed our hypothesis: greater optimism and less anxiety in the peri-transplant period were significantly associated with fewer DTE in autologous HCT recipients, although this relationship was no longer significant with the reduced sample size evaluating only subjects who completed their survey by Day +3. The effect remained similar, however, as indicated by the standardized estimates. Fewer DTE would be expected to result in a shorter period of extreme infectious susceptibility and increased survival.These results suggest one possible mechanistic explanation to the growing body of literature on the effects of psychosocial factors on HCT outcomes We did not observe significant findings with allogeneic transplant patients; we suggest that the additional significant physiological burdens involved in their treatment might diminish the impact of psychosocial factors on DTE for this group. Another possibility is that the psychosocial effect may be somehow imprinted on the transplanted cells themselves, preventing the observation of this effect when the donor psychosocial status is unknown, as occurs in this study with allogeneic transplantation. Finally, allogeneic recipients take immunosuppressive agents to mitigate graft versus host disease; these may also mask the relationship between psychosocial factors and immune outcomes.Our results are consistent with prior work demonstrating an impact of anxiety on immune recovery post-transplant There are some significant limitations to our study. We investigated a very heterogeneous group ; future analyses should either be powered to control for these differences or examine a more homogeneous group. Our most significant limitation is the variability in timing of when the baseline surveys were completed, which when restricted to those who filled out their surveys by the time of engraftment resulted in psychosocial factors and DTE not being significantly associated. This could mean that in fact knowledge of engraftment influenced optimism and anxiety; however, there are three reasons why this knowledge may not have significantly influenced anxiety or optimism in our study. First, we evaluated trait and not state anxiety, with studies demonstrating substantial stability of both the short- (20–100 days) and long-term (years) STAI-T measure In conclusion, our findings suggest that optimism and anxiety may be associated with time to neutrophil recovery in autologous stem cell transplant patients, though this relationship was no longer significant with the reduced sample size evaluating subjects completing their psychosocial surveys by Day +3, with more favorable peri-transplant psychosocial factors associated with shorter time to neutrophil recovery. Further research is needed with larger and more homogeneous cohorts of HCT patients with consistent baseline sampling to investigate the impact of psychosocial factors on DTE and other immunologic transplant sequelae with the goal of improving outcomes in this physically and psychologically stressed population.