Striatum is the critical structure in goal directed behavior. Striatal processing of the input to striatal structures under the presence of dopamine yields the primary output of the action selection loop in the basal ganglia. This primary output travels through the other structures active for the action selection loop in the basal ganglia and produces the stimulation to the motor circuits of the brain via thalamus. It is not wrong to say that action selection starts and ends in the striatum. The recent research shows that both the ventral (nucleus accumbens) and the dorsal (putamen) striatum take part in decision making processes . MidbraiA computational model is developed to demonstrate that through the striato-nigro-striatal pathway, limbic regions have impact on the motor regions of the basal ganglia and also the integration of the outputs of dorsal and ventral striatal structures produces the resulting output of the basal ganglia action selection loop. This model takes into account the physiological properties of neurons in each basal ganglia structure and the effects of the ion channels on the cell membrane to state a more realistic processing unit. Hodgkin-Huxley type conductance based neuron models are used in order to demonstrate the effects of ion channel currents on the functioning of a neuron. Striatal neurons are modeled as two groups which have D1 or D2 type dopamine receptors. Dopamine input from midbrain neurons acts on the ion channels and stimulates the D1 neurons while inhibiting the D2 neurons. Thus a computational model is obtained which can produce different types of action potentials. This computational model was partially presented at  and focu


Smilisca fodiens) across its geographical distribution. We employed Ecological Niche Modeling (ENM) to perform a monthly analysis of spatial variation of suitable climatic conditions , and then evaluated the geographical correspondence of monthly projections with the occurrence data per month. We found that the species activity, based on the species' occurrence data, corresponds with the latitudinal variation of suitable climatic conditions. Due to the behavioral response of this fossorial frog to seasonal climate variation, we suggest that precipitation and temperature have played a major role in the definition of geographical and temporal distribution patterns, as well as in shaping behavioral adaptations to local climatic conditions. This highlights the influence of macroclimate on shaping activity patterns and the important role of fossorials habits to meet the environmental requirements necessary for survival.The importance of climatic conditions in shaping the geographic distribution of amphibian species is mainly associated to their high sensitivity to environmental conditions. How they cope with climate gradients through behavioral adaptations throughout their distribution is an important issue due to the ecological and evolutionary implications for population viability. Given their low dispersal abilities, the response to seasonal climate changes may not be migration, but behavioral and physiological adaptations. Here we tested whether shifts in climatic seasonality can predict the temporal variation of surface activity of the fossorial Lowland Burrowing Treefrog ( Ecological niches can be defined as the set of conditions within which a species can maintain populations without immigrational input But what about organisms with a low dispersal ability like amphibians? Could it be signs of behavioral adaptations due to the effects of seasonal climate within the distributional range of these ectothermic organisms? Despite the high sensitivity of amphibians to environmental variables Smilisca fodiens) has the northernmost distribution of the family; its current distribution encompasses a significant climatic gradient, from the desert scrub in south-central Arizona Smilisca fodiens spends a period of the year inside underground burrows, until the climatic conditions trigger a brief and explosive period of surface activity Smilisca fodiens to reach such a high latitudinal range, far above the northern limit of the remaining hylids. We suggest that evolving a fossorial behavior allows this species to inhabit temperate regions while retaining its climatic niche.Among amphibians, the Hylid frog family is widely distributed around the world Smilisca fodiens across its geographical distribution. We model the ecological niche of the species based on the month with the most suitable conditions for the species activity (i.e. July) and project it on the climatic conditions of the remaining months of the activity period (defined by the occurrence data). We evaluate the geographical correspondence of monthly projections with the occurrence data per month and discuss how a behavioral trait associated to fossorial activity can favor the conservation of the climatic requirements of a species with low dispersal ability inhabiting a marked climatic gradient.In this study, using coarse-scale ecological context of species niches S. fodiens is fossorial, we assumed that the records ensured that the collected organisms were found on the surface in suitable environmental conditions. We used records with geographic information (latitude-longitude); and those with no geospatial information were georeferenced using BioGeomancer (http://www.biogeomancer.org) and the Georeferencing Calculator (http://manisnet.org/gci2.html). Each locality record was verified in ArcView 3.2 We compiled locality occurrence records from three sources: biological collections ; published literature http://www.worldclim.org/) and are the result of the interpolation of monthly averages from weather stations throughout the world, from 1950 to 2000 http://eros.usgs.gov/). Resolution of all layers was 30 arc-seconds (∼1 km2). The selection of the climatic variables was based on their relevance for amphibians We employed a set of five variables for each of the analyzed months (four climatic and one topographic). The layers of maximum and minimum monthly temperature (Tmin and Tmax), monthly mean temperature (Tmean) and monthly total precipitation (Prec) were obtained from the WorldClim project , assuming that this month meets the climatic conditions that are the most suitable for species activity. Of the 95 occurrence data points used for the model, only four were outside the temporal interval (1950–2000) of the climatic layers. Thus, we expect no effects due to the climate variation outside these five-decades that compromise the reliability of the potential niche obtained for July. Finally, the climatic niche was then projected on the climatic conditions of the remaining months of the period of activity: May, June, August, September, October, November and December (months in which we found at least one occurrence data point).n simulations, where the result is an index of how favorable the climatic conditions are to species requirements We employed two automatic learning algorithms: the Genetic Algorithm for Rule-set Prediction (GARP) and the maximum entropy approach (Maxent). For GARP models we used a desktop version which operates under a stochastic process where classifiers  compete to select solutions that identify the presences and the pseudoabsences −5).Maxent fits a probability distribution for occurrence of the species to the set of pixels across the study region subject to the appropriate constraints. In ecological niche modeling these constraints are the expected value of each feature, which should match its empirical average. We assigned 80% of the occurrence data points to formulate the model parameters. For Maxent models we used the default parameters  ratios The distributions obtained by ENM generally over predict because the model does not consider the factors that may have limited biologically, historically and geographically the occupation of such niches kappa2 function in the irr package p-value less than 0.05. The amount of predicted area was estimated based on the thresholds of agreement described above and presented as percentages of number of pixels.The temporal variation of suitable climatic conditions throughout the area of distribution was evaluated based on both the degree of correspondence between the monthly projections and occurrence data, and the estimation of the percentage of predicted area for each month. We determined the amount of monthly occurrence data that coincided with the monthly projections and estimated the kappa coefficient Spatial Analyst extension of ArcView 3.2. Finally, we compared the monthly variation in the precipitation and minimum temperature ranges performing a Mann–Whitney U-test  with the wilcox.test function in the stats package To describe the environmental space for species activity, we analyzed the ranges of precipitation and minimum temperature  that are suitable for the species activity based on the climatic information of the occurrence data. Because the occurrence data points of July are widely and evenly spread along the distribution area of the species, we used them to demonstrate that the climatic conditions suitable for activity spatially vary throughout the year. Thus we analyzed the climate ranges of July points both for the dry season, when activity is not reported (January to April), and for the season in which the period of activity is favored (May to December), and then were compared with the climate ranges of remaining months of the activity period. For this we used the We found that the geographic distribution of suitable climatic conditions for the activity of the species varies temporally . We obseThe occurrence data for each month of the activity period (i.e. May to December) showed a high geographical correspondence with the variation of suitable conditions throughout the study region  did not match that described for the activity period (May to December) . FinallySmilisca fodiens has a range of climatic conditions wider that the species can tolerate, so it can be suggested that the species evolved behavioral We found that the activity of the species outside burrows is predicted by climatic conditions  and thatSeveral local-scale studies in fossorial anurans have shown the influence of microclimatic conditions over the explosive surface activity of individuals Smilisca fodiens and the annual latitudinal variation of suitable conditions could reflect a behavioral adaptation in order to retain its physiological tolerance ranges. For instance, amphibians from xeric environments rely on rainy conditions to avoid desiccation due to the high permeability of the skin The fossorial behavior is a common strategy among temperate anurans Smilisca fodiens. Such changes appear to be a strong selective force in species adaptation, as it has been shown when the response rate of some traits  increase its selective values at the optimums of the environmental tolerance range of species, particularly, when there is an increase in the spatial and temporal heterogeneity of environment between generations Local-scale studies of fossorial anurans Smilisca group Smilisca fodiens will face a reduction in its already restricted activity period for feeding and breeding, and that metabolic responses during dormancy in cold periods can be compromised, affecting the survival of the species. In this context, it will be particularly important that future studies address the possible impact of the shifts in climatic patterns over fossorial anurans.Based on the importance of precipitation on the activity of this species, the increase in aridity during the Pleistocene along its geographical range, could have favored its differentiation within the The important role that climatic conditions have on the distribution patterns of anurans is well known, but the role of spatial and temporal climatic variation in the activity of fossorial anuran species is poorly understood. Despite this analysis focusing on a single species, the life history traits and the evolutionary history of the Lowland Burrowing Treefrog allows us to project our findings to other ectothermic organisms with low dispersion ability. We expect that approaches based on the analyses of ecological niches can contribute and enhance the understanding of current patterns and its evolutionary processes. All of these as part of a more general theory of seasonality of the ecological niches.Acknowledgments S1Collections and institutions included in HerpNET and GBIF that provided historical occurrence.(DOCX)Click here for additional data file.


Anatomical comparisons of the ear region of baleen whales (Mysticeti) are provided through detailed osteological descriptions and high-resolution photographs of the petrotympanic complex  of all extant species of mysticete cetaceans. Salient morphological features are illustrated and identified, including overall shape of the bulla, size of the conical process of the bulla, morphology of the promontorium, and the size and shape of the anterior process of the petrosal. We place our comparative osteological observations into a phylogenetic context in order to initiate an exploration into petrotympanic evolution within Mysticeti.Balaenoptera musculus; confluence of fenestra cochleae and perilymphatic foramen in Eschrichtius robustus), and several mysticete clades are united by derived characteristics. Balaenids and neobalaenids share derived features of the bulla, such as a rhomboid shape and a reduced anterior lobe (swelling) in ventral aspect, and eschrichtiids share derived morphologies of the petrosal with balaenopterids, including loss of a medial promontory groove and dorsomedial elongation of the promontorium. Monophyly of Balaenoidea  and Balaenopteroidea  was recovered in phylogenetic analyses utilizing data exclusively from the petrotympanic complex.The morphology of the petrotympanic complex is diagnostic for individual species of baleen whale (e.g., sigmoid and conical processes positioned at midline of bulla in This study fills a major gap in our knowledge of the complex structures of the mysticete petrotympanic complex, which is an important anatomical region for the interpretation of the evolutionary history of mammals. In addition, we introduce a novel body of phylogenetically informative characters from the ear region of mysticetes. Our detailed anatomical descriptions, illustrations, and comparisons provide valuable data for current and future studies on the phylogenetic relationships, evolution, and auditory physiology of mysticetes and other cetaceans throughout Earth's history. The mammalian petrotympanic complex houses the organs of hearing and balance and in cetaceans is partially or completely detached from the rest of the basicranium Unlike the odontocete petrotympanic complex, the petrotympanic bones in mysticetes are firmly attached to one another via two bony connections: the anterior and posterior pedicles . DevelopNot surprisingly, the mysticete petrotympanic bones comprise a morphologically and functionally complex structure that preserves a wealth of anatomical information useful in examining patterns of adaptation and macroevolution. As recently discussed by O'Leary Other important works utilizing a comparative anatomical approach to investigate cetacean hearing adaptations and evolution include research on the tympanic bulla of stem cetaceans A cursory review of the literature reveals a somewhat confusing array of anatomical terms for the various salient morphological parts and regions of the mysticete petrotympanic complex. Although several recent reports With over 35 years elapsing since the seminal study by Kasuya All of the specimens that were examined are housed in curated museum collections . The speAs with terrestrial mammals, the mysticete ear is divided into three major anatomical divisions: the outer ear from the external environment to the tympanic membrane, the middle ear from the tympanic membrane to the ventrolateral (tympanic) surface of the petrosal, and the inner ear including the organs of balance and hearing within the petrosal bone itself. Although the present study is focused on the morphology of the middle ear and its structures in mysticetes, we also provide an overview of the outer and inner ears as an introduction to the entire system.Unlike the outer ear of terrestrial mammals, all extant cetaceans lack an external pinna surrounding the external auditory meatus, which connects the tympanic membrane to the surrounding environment. At the proximal end of the mysticete external auditory meatus is a dense waxy plug that nearly fills the entire lumen of the meatus . The proIn vivo this region of the tympanic cavity is occupied by a vascular structure called the corpus cavernosum tympanicum that may expand to fill the bullar cavity during diving Within the middle ear, the bullar portion of the tympanic cavity is formed by the deeply excavated region between the involucrum and lateral wall of the tympanic bulla . NumerouCaperea); the stapedial fossa is often large and hemispherical; the malleolar fossa is indistinct in contrast to well formed fossa in odontocetes ; the ossicular chain of stapes, incus, and malleus is constructed as in odontocetes with the malleus fused to the tympanic bulla via the processus gracilis.In mysticetes the promontorium of the petrosal is typically domed and not flattened as in odontocetes; the fenestra cochleae and fenestra vestibuli are well separated from each other as in odontocetes and unlike the condition in terrestrial artiodactyls where the two openings are more closely positioned; the secondary facial foramen and facial sulcus is generalized in its form and position  rotates its head at slower velocities than the terrestrial artiodactyl Bos taurusThe anatomy of the mysticete inner ear as currently understood is summarized in several reports The endocranial surface of the mysticete petrotympanic complex is characterized by a number of important features including the rough and jagged surface texture of this region, the closely appressed endolymphatic and perilymphatic foramina, and variable development of the internal auditory meatus , 5. The Ontogeny provides another source of petrotympanic morphologic variation that can only briefly be described here. The tympanic bullae of neonate and yearling individuals typically possess smooth and rounded external surfaces in contrast to the roughened and sharply angled surfaces of adult individuals. This textural difference is especially prominent on the involucral  and medial surfaces of the bulla. In the former the involucral surface is smooth and lacks the strong transverse creases of adults, and in the latter the main and involucral ridges are low and poorly defined in comparison to the much more prominent ridges of adults. The petrosals of neonate and yearling individuals typically possess short anterior and posterior processes relative to the adult condition of distinctly longer anterior and posterior processes. In addition, the endocranial surface of the pars cochlearis in neonates and juvenile individuals typically is low and extremely porous rather than extended dorsally into the cranial hiatus. Further, the internal auditory meatus of neonates and juvenile individuals is broadly subdivided into distinct foramina for CN VII and CN VIII by a prominent crista transversa. In adult individuals the internal auditory meatus generally consists of a single common opening, at the bottom of which lies the two foramina separated by a deeply recessed crista transversa .Tursiops truncatus). Although we largely accept their suggestions , and not a specific bone in many studies focused on mammals A structure on the lateral side of the petrosal referred to as the superior process in many cetacean studies is homologous to the tegmen tympani of terrestrial mammals A pair of openings that penetrate the promontorium, the fenestra cochleae and fenestra vestibuli, often are referred to as the fenestra rotunda (round window) and fenestra ovalis  respectively based on the shapes of the structures . However, two openings that transmit branches of the trigeminal nerve, namely the foramen rotundum and the foramen ovale, are described in very similar terms. The similarity in these names can lead to confusion Lastly, many descriptions of the ear regions of whales describe a structure on the promontorium of the pars cochlearis that is identified in numerous studies as the ‘caudal tympanic process’ The following morphologic descriptions include combinations of apomorphic and pleisomorphic character states that together provide a useful characterization of the petrotympanic anatomy of individual taxa. For each taxon we describe the tympanic bulla first followed by a description of the petrosal. In addition the descriptions are constructed in a parallel format to facilitate anatomical comparisons. We have also included digitial images of tympanic bullae and petrosals for each taxon, incorporating four standard views for each element with salient features labeled. A taxonomic order overlies the description section and is based on the generally recognized clades within crown Mysticeti .Balaena mysticetus is rhomboid shaped with a distinct anteromedial corner. The medial half of the ventral surface is dorsoventrally compressed to form a longitudinal furrow, a feature also seen in species of Eubalaena. The anterior lobe (new term) of the bulla is distinctly smaller than the posterior lobe, the two regions being separated by a deep, obliquely directed lateral furrow. Again, species of Eubalaena share this feature. The main ridge . The hiatus Fallopii opens through the ventral surface of the promontorium medial to the juncture between the promontorium and the anterior process. The groove for the tensor tympani muscle is deeply recessed along this same juncture. The epitympanic recess is broad and smooth and lacks a clearly defined malleolar fossa. The posterior cochlear crest is short and thin with a pointed tip that only slightly extends over the ovoid, relatively shallow stapedial fossa. The stapedial fossa is separated from the facial nerve sulcus by a thin longitudinal ridge. The composite posterior process is relatively broad and short in comparison to the narrower and more elongated processes of balaenopterids. The facial nerve sulcus in Balaena is distinct and broadly open.In ventral view , the flaEubalaena the suprameatal region is elevated and continuous between the promontorium and tegmen tympani. The dorsolateral surface of the tegmen tympani is broadly rounded.In dorsal view  the juncIn posterior view the fenestra cochleae is large and recessed into the promontorium with a narrow dorsomedially directed embayment extending towards the dorsomedial rim of the promontorium . The fenIn dorsomedial view  all of tEubalaena species given our limited samples for each taxon and mixed semaphorants. We have described morphologic variation that may be species specific when more specimens are studied.We provide below a composite description of the three E. japonica are generally larger than other species . A relatively deep sulcus for CN VII extends laterally on the posteroventral side of the posterior process. The globular promontorium is relatively longer anteroposteriorly as in Eubalaena and unlike the shorter promontorium in Balaena. However, the transverse width of the promontorium more closely resembles Balaena than Eubalaena. The ventral surface of the promontorium is rounded and convex. As in balaenids there is a distinct, but irregular promontorial groove below the dorsomedial rim of the promontorium. In turn, the dorsomedial rim of the promontorium is marked by distinct columnar bony extensions. The tympanic opening for the facial nerve is not in its common and typical location adjacent to the fenestra vestibuli and at the head of the facial nerve sulcus, but instead is positioned well anteriorly near the anterior margin of the pars cochlearis and medial to the juncture between the promontorium and anterior process. The opening varies from an elongate slit with subtle sulci extending both anteriorly and posteriorly  to a circular opening with more distinct anterior and posterior sulci . The posterior sulci likely transmitted the hyomandibular branch of CN VII, while the greater petrosal nerve traversed the anterior sulcus. Whether the tympanic opening is homologous with the hiatus Fallopii, or if the hiatus Fallopii is absent all together in Caperea, remains unclear at this time. The origin of the tensor tympani muscle has no bony landmarks . The epitympanic region is occupied by an elliptical fossa that may accommodate the malleus. The posterior cochlear crest is short but thick and forms only the extreme anterior portion of the floor of the large and broadly hemispherical stapedial fossa. The stapedial fossa is separated from the facial nerve sulcus by a low longitudinal ridge.In ventral view , the flaIn dorsal view  the parsIn posterior view  the feneIn dorsomedial view  the fourB. bonaerensis, the tympanic bulla of B. acutorostrata is small  external mastoid apex. The body of the posterior process is compressed anteroposteriorly and expanded dorsoventrally. A relatively shallow sulcus for CN VII extends laterally on the ventral side of the posterior process.In ventral view , the flachlearis . The venIn dorsal view  the parsA much broader anterointernal sulcus is present on the anteromedial edge of the anterior process and extends to the apex of the process. When the petrosal is in place within the cranial hiatus, this sulcus forms a portion of the canal for transmission of the mandibular branch of CN V as it passes over the pterygoid fossa and descends towards the dentary.In posterior view  the feneIn dorsomedial view  the inteB. bonaerensis is morphologically very similar to that of B. acutorostrata, although slightly larger  flange posterior to the fenestra cochleae. The dorsolateral surface of the posterior cochlear crest is thin and concave and forms the floor of the relatively large and hemispherical stapedial fossa. The composite posterior process is very long, especially in adults. The body of the posterior process is compressed anteroposteriorly and expanded dorsoventrally. A relatively deep sulcus for CN VII extends laterally onto the ventral side of the posterior process and in some specimens is nearly completely enclosed by a bony roof.In ventral view  the flanchlearis . The proB. acutorostrata is not obvious on specimens of B. musculus. The anterointernal sulcus is absent from the anteromedial edge of the anterior process.In dorsal view  the parsIn posterior view  the feneen echelon arrangement separated by a thin, mediolaterally oriented bony septum. In this view the sharply truncated dorsomedial rim of the promontorium is clearly evident with a rim of cancellous bone marking the area where the dorsomedial bony extension of the pars cochlearis has been broken away.In dorsomedial view  the inteB. omurai is intermediate in size  the anterior process is broadly attached to the anterior margin of the promontorium with a convex dorsomedial rim. The medial margin of the anterior process is relatively smooth, but in some specimens possesses short, irregular, medially directed bony extensions at the point of contact between the promontorium and anterior process. This is similar to the condition in some specimens of B. musculus, although in the latter taxon the bony extensions generally are more elaborate. The anteroposterior length of the anterior process is greater than that of the pars cochlearis  flange posterior to the fenestra cochleae. The dorsolateral surface of the posterior cochlear crest is thin and concave and forms the floor of the relatively large stapedial fossa. Unlike the condition in B. musculus the stapedial fossa is not excavated into the posterior cochlear crest and is separated from the secondary facial sulcus. The composite posterior process is very long, especially in adults. The body of the posterior process is compressed anteroposteriorly and expanded dorsoventrally. A relatively deep sulcus for CN VII extends laterally onto the ventral side of the posterior process and in some specimens is nearly completely enclosed ventrally by a bony floor.In ventral view  the flanchlearis . The proIn dorsal view  the parsIn posterior view  the feneen echelon arrangement separated by a thin, mediolaterally oriented bony septum. In this view the sharply truncated dorsomedial rim of the promontorium is clearly evident with a rim of cancellous bone marking the area where the dorsomedial bony extension of the pars cochlearis has been broken away.In dorsomedial view  the inteM. novaeangliae is intermediate in size and distinctly inflated as reflected in both the broadly convex ventral surface and the enlarged tympanic cavity  but less so in others . Irregular bony projections occur on the anteromedial portion of the anterior process in more immature specimens that possess a slight anteromedial embayment between the anterior process and promontorium. A broad, anteroposteriorly oriented sulcus occurs in some specimens on the ventral surface of the anterior process between the groove for the tensor tympanii and the anterior bullar pedicle. The anteroposterior length of the anterior process is greater than that of the pars cochlearis  as its sister taxon , but balaenopteroid relationships were unresolved. However, a monophyletic Balaenopteroidea was recovered as a polytomy . These results support the Balaenoidea plus Balaenopteroidea hypothesis C. marginata plus Balaenopteroidea hypothesis . We also provide a brief discussion concerning the lack of resolution within Balaenopteridae.Mammalodon and Eomysticetus  and three unambiguous synapomorphies from the petrotympanic complex. Those characters include elongation of the main ridge to the anterior end of the bulla  share the rhomboid shape of the tympanic bulla  and orientation of the posterior process at a right angle to the long axis of the pars cochlearis . Neither of these character states were observed in any other extant mysticete that we examined for the currenty comparative study. The short anterior lobe  and the weakly developed conical process of the tympanic bulla  that characterize balaenids and neobalaenids likely are other synapomorphies for Balaenoidea, although we were unable to accurately measure these features for the outgroup taxa in order to polarize the two characters.Although most morphological studies recover balaenoid monophyly teroidea . BalaenoC. marginata with Balaenopteroidea was supported by six unambiguous synapomorphies. Of those six characters, one was taken from the ear region , and we included that character in our analysis (character 27 of our study) as well. However, we differ in our interpretation of pars cochlearis elongation in C. marginata (scored as absent here but as present in the previous study). The transverse elongation of the pars cochlearis that characterizes the petrosal of balaenopteroids is associated with a medial flaring of the promontorium  is much more globular, and almost boxy (C. marginata (B. musculus (as opposed to the flattened promontorium of B. bonaerensis). It is unlikely that rescoring the character for C. marginata would overturn the Marx's hypothesis A monophyletic Balaenoidea is consistent with most previous morphological studies. In the morphological analysis disputing balaenoid monophyly proposed by Marx um e.g., . In the ost boxy  and 9. Iarginata  appears Monophyly of Balaenidae has been well supported by both molecular and morphological data en echelon arrangement of the perilymphatic and endolymphatic openings , and an acute angle between the posterior process and the flange of the ventrolateral tuberosity . It should be noted that several of these characters, such as shape of the apex of the anterior process and attachment of the process to the promontorium, vary within the genus Balaenoptera  is less controversial than Balaenoidea, but the results of at least one morphological study enoptera .E. robustus and M. novaeangliae. In trees 1 and 2, these taxa form a clade nested among other balaenopteroid species . In contrast, M. novaeangliae was placed as the sister taxon to all species of Balaenoptera with E. robustus excluded from Balaenopteridae all together in tree 3 . If character 45 is excluded from the phylogenetic analyses, both M. novaeangliae and E. robustus fall outside a clade composed of all species of Balaenoptera  with Balaenopteroidea, or place eschrichtiids (E. robustus) with Balaenoidea.It is clear from our analysis that the petrotympanic complex exhibits a phylogenetic signal, even if only at a gross level. The morphology of the auditory region alone can support monophyly of the two traditional lineages of Mysticeti, which are Balaenoidea and Balaenopteroidea, and which is a result that follows traditional interpretations of mysticete relationships while competing with more recent studies that either place neobalaenids  Mammalodon colliveri (toothed mysticetes) and Eomysticetus whitmorei (edentulous mysticete) were chosen as outgroup taxa. Bootstrap analyses included 1000 pseudoreplicates.We identified 48 morphological characters within the petrotympanic complex  and codeFigure S1Three most parsimonious trees recovered from phylogenetic analysis of 48 petrotympanic characters. Major difference between topologies lies with Eschrichtius robusts and Megaptera novaeangliae (in bold).(TIFF)Click here for additional data file.Figure S2Six most parsimonious trees recovered from phylogenetic analysis of petrotympanic characters excluding #45 .(TIFF)Click here for additional data file.Table S1List of extant mysticetes studied .(PDF)Click here for additional data file.Table S2Measurements (mm) of tympani bulla of balaenid and neobalaenid species.(PDF)Click here for additional data file.Table S3Measurements (mm) of tympanic bulla of balaenopterid and eschrichtiid species.(PDF)Click here for additional data file.Table S4Tympanic bulla anterior lobe measurements (mm) among mysticetes.(PDF)Click here for additional data file.Table S5Tympanic bulla conical process measurements (mm) among mysticetes.(PDF)Click here for additional data file.Table S6Petrosal measurements (mm) among mysticetes and reated taxa.(PDF)Click here for additional data file.Table S7Data matrix of petrotrympanic characters scored for extant mysticetes used in phylogeneti analyses. Matrix can be downloaded from project page associated with this manuscript at MorphoBank (www.morphobank.org).(PDF)Click here for additional data file.Text S1Dichotomous key for identifying extant species of mysticetes using the petrotympanic complex.(PDF)Click here for additional data file.Text S2Phylogenetic characters derived from the petrotympanic complex of extant mysticetes. Further information can be found on the project page associated with this study at MorphoBank (www.morphobank.org).(PDF)Click here for additional data file.


Among a general lack of awareness of scoliosis, the incidence of Adolescent Idiopathic Scoliosis (AIS) in the United Arab Emirates is not known although efforts are currently being made to remedy this. The Emirati people have a unique and well-structured culture with strong family relationships and might be considered a closed group. Consequently, there are some factors within this group that suggest that the incidence of AIS might be higher than in other parts of the world. In this study, the incidence of ligamentous laxity among young Emirati women was measured because this has been associated many times previously with AIS and casual observation has suggested that ligamentous laxity is prevalent among many young Emirati women.The degree of extension of the middle metacarpo-proximal-phalanx joint and thumb abduction were measured on both hands using standard, previously reported techniques of 100 randomly-selected, young Emirati women. The results were compared with similar published data from the United Kingdom.The results showed that there was a higher incidence of ligamentous laxity among the emirati population in both the degree of extension of the middle metacarpo-proximal-phalanx joint as well as thumb abduction when compared to the values from the UK.These results suggest that the incidence of AIS in the UAE (when determined) might be expected to be greater than in other parts of the world due to a higher incidence of ligamentous laxity among the susceptible population.


In particular, we compared the electric potential profile of the membranes of spinal ganglion and neuroblastoma cells, during the resting and action potential (AP) states. The spinal ganglion neurons represent healthy cells, while neuroblastomas denote tumorous neurons.Electrical signals underlie the propagation of information in the nervous system. It is known that neuronal cells can generate electric potentials by diffusing ions across the neuronal membrane. We have previously studied the effects of electric charges fixed onto the inner surface of the membrane, on the potential of the membrane surfaces of healthy and cancerous neuronal cells ,2. BasedTo analyze the electric potential profile of neuronal membranes, we numerically solved the Poisson-Boltzmann equation ,3. The mz axis from the extracellular region to the surface of the glycocalyx. The decay of the potential is more expressive for the neuroblastoma than for the ganglion neuron. An interesting observation is that the electric potential continues to decrease across the glycocalyx region of the spinal ganglion neuron. This however does not occur for the neuroblastoma cells, whose potential does not change in this region of the membrane.For the resting and AP states of spinal ganglion neurons and neuroblastoma cells, simulation results indicate that the electric potential significantly decreases along the Because there is no electric charge within the lypidic bilayer, our results demonstrate linear variations of the potential across the bilayer of neuronal membranes. Furthermore, the intracellular potential of both spinal ganglion neurons and neuroblastoma cells exponentially increases from the inner membrane surface to the bulk cytoplasmic region during the resting state. However, during the AP state, the electric potential remains unchanged in the cytoplasm.Our simulation results match those obtained for the membrane of the squid axon , whose m


The propyhlaxy programme for the families with high hereditary risk of malignant cancers organized and guided by the Ministry of Health of Poland. Our data are based on the activity of the ZOZ “SALVE”, one of three units operating in the Lodz district in Poland. Over 600 questionnaires produced by patients with problems of in-family cases of cancer (including ovary cancers and/or breast cancer) were collected between mid-2010 to the end of the 2011. Four cases of male breast cancer were recorded and screened across the clinically recorded family data for these patients. It appeared that these cases could not be fully explained in accordance with the current concept of the family cases of cancers. These discrepances could be either related to the faulty selection criteria or to the highly differentiated male population suffering the breast cancer. The diagnostic potential within the “Module 1: early detection of malignant cancers in hereditary high-risk families with ovary cancer and breast cancer“ is discussed and evaluated in practical terms including regulatory/ legislation aspects. Supported by the Ministry of Health of Poland.


We describe and expand on a novel computational approach to reduce detailed models of central pattern generation to equationless return mapping for the phase lags between the constituting bursting interneurons .Such mappings are then studied geometrically as the model parameters, including coupling properties of inhibitory and excitatory synapses, or external inputs are varied. Bifurcations of the fixed points and invariant circles of the mappings corresponding to various types of rhythmic activity are examined. These changes uncover possible biophysical mechanisms for control and modulation of motor-pattern generation. Our analysis does not require knowledge of the equations that model the system, and so provides a powerful new approach to studying detailed models, applicable to a variety of biological phenomena beyond motor control.Motifs of three coupled cells are a common network configuration including models of biological central pattern generators. We demonstrate our technique on a motif of three reciprocally coupled, inhibitory and excitatory, cells that is able to produce multiple patterns of bursting rhythms. In particular, we examine the qualitative geometric structure of two-dimensional maps for phase lag between the cells. This reveals the organizing centers of emergent polyrhythmic patterns and their bifurcations, as the asymmetry of the synaptic coupling is varied. The presence of multistability and the types of attractors in the network are shown to be determined by the duty cycle of bursting, as well as coupling interactions.


The infection times of individuals in online information spread such as the inter-arrival time of Twitter messages or the propagation time of news stories on a social media site can be explained through a convolution of lognormally distributed observation and reaction times of the individual participants. Experimental measurements support the lognormal shape of the individual contributing processes, and have resemblance to previously reported lognormal distributions of human behavior and contagious processes. The analysis of human social dynamics stemming from the emergent effects of individual human interactions has recently created a spur of research activity. Encompassing a wide area ranging from the propagation of opinions, epidemic spreading of information and innovation across groups of individuals The analysis of the observed temporal distributions of online human activity data such as the inter-arrival and forwarding times of email Lognormal distributions There are a few general processes that lead to a lognormal random variable. A lognormal random variable is defined In this paper, we study the inter-arrival time of retweets in Twitter and the spreading times on Digg. Both times reflect human interaction through communication technology. We show that this relatively new type of human interaction is lognormally distributed.In order to spread information, such as forwarding a message or news item on a social media platform, three consecutive processes take place as shown in In the following discussion, time measurements from the microblog service Twitter and the (former) social news aggregator Digg.com are used to explore the spread of information on online social media. For the case of Twitter we measure Measurements of the network time In the following, we make two basic hypotheses:We assume that the random variable We make the hypothesis based on previous findings , and  as the observation time (colored orange in the insets). The measured and fitted observation time parameters The analysis of the experimental data shows that both lower and upper bound of observation and reaction time are following a lognormal distribution, thereby confirming our initial hypotheses for the spreading time The analysis of spreading times was based on two datasets, a collection of initial original posts and their corresponding retweets on the microblog Twitter, and five year trace of stories and votes submitted to the social media aggregator Digg.com. Both datasets were collected from the providers' webpages and API interfaces and contain only publicly available information. The former dataset of 20.5 million tweets was constructed in a two step process: Starting from an initial 1% random sample of all tweets published within Twitter, we automatically retrieved for each of these initial tweets all further subsequent reappearances of these messages thereby generating forests of individual message spreads The analysis and the experimental data point to lognormal distributions as an explanation of the temporal distributions observed in epidemic spreading online. This finding is not per se surprising as lognormal distributions have for a long time been observed in and connected to human behavior, which is also driving the spread of information and innovation online.The analogue to the reaction time Similar lognormal patterns have been discovered across domains for the equivalent of the observation time This general notion of the lognormally distributed duration of human activities and associated spreading tasks are also repeatedly found across other domains, for example in the duration of strikes The lognormal distribution regularly appears in the broader context of universal human activities and behavior. When tracing the mobility of cell phone handsets, Barcelo and Jordan Similarly, a variety of such lognormally distributed properties of populations have been discovered, such as in the distribution of incomes or marriage ages Based on a huge number of measurements in Twitter and Digg, we found that human related activities such as the observation time


In adult mammals, under physiological conditions, neurogenesis, the process of generating new functional neurons from precursor cells, occurs mainly in two brain areas: the subgranular zone in the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) lining the walls of the brain lateral ventricles. Taking into account the location of the SVZ and the cytoarchitecture of this periventricular neural progenitor cell niche, namely the fact that the slow dividing primary progenitor cells (type B cells) of the SVZ extend an apical primary cilium toward the brain ventricular space which is filled with cerebrospinal fluid (CSF), it becomes likely that the composition of the CSF can modulate both self-renewal, proliferation and differentiation of SVZ neural stem cells. The major site of CSF synthesis is the choroid plexus (CP); quite surprisingly, however, it is still largely unknown the contribution of molecules specifically secreted by the adult CP as modulators of the SVZ adult neurogenesis. This is even more relevant in light of recent evidence showing the ability of the CP to adapt its transcriptome and secretome to various physiologic and pathologic stimuli. By giving particular emphasizes to growth factors and axonal guidance molecules we will illustrate how CP-born molecules might play an important role in the SVZ niche cell population dynamics. The adult subventricular zone (SVZ) neural stem cell niche, also designated as subependymal zone to distinguish from the embryonic SVZ, is the major source of novel neurons in the adult brain  an apical surface  composed of a large number of microvilli of variable length that extensively increases the contact area with the CSF; (2) a smother basolateral membrane ; and (3) lateral membranes, the surface contact area between adjacent epithelial cells. At the most apical portion of the lateral membranes the existence of tight junctions limits the paracellular passage of blood derived cells and proteins , is well described to promote growth and neuronal survival in the mouse developing cortex , adult SVZ derived cells form neurospheres that display multipotent and self-renewal properties  and its apical interface (the CNS side). On the other hand, any response the CP mounts to external stimuli will ultimately reflect in its secretome, and hence in the CSF that surrounds the brain parenchyma. In fact, since the CP epithelial cells are equipped with transporters for several proteins and metabolites, pathological damage to the CP itself will alter CSF composition and ventricular volume, as in the case of hydrocephalus , or might function as potential rescue mechanisms for brain parenchyma lesions , will be a key issue in adult neural stem cell research in the future. In fact, modulating the CP-CSF nexus in pathologies of the central nervous system could become an important aspect in the usage of endogenous/exogenous neural progenitor cells for stem cell based therapies in the brain.Under basal normal physiological conditions the CP displays the ability to express several genes encoding for proteins known to promote proliferation, differentiation, and survival of neural progenitor cells. These proteins are secreted toward the CSF, which is as a route for the delivery of CP-born proteins/molecules to the SVZ. 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.


Multiple biomarkers have been proposed for identifying patients at risk of developing the syndrome of acute kidney injury (AKI) . These bWe measured serum and urinary NGAL and urinary hepcidin in patients admitted to the ICU of a tertiary referral hospital with SIRS and either oliguria or a 25 μmol/l serum creatinine increase within 48 hours of admission. We used point-of-care creatinine measurements to identify the maximum RIFLE category of AKI within the first 5 days of enrolment. We corrected both urinary biomarkers for urinary creatinine. We calculated the reciprocal of hepcidin measurement and noted if serum NGAL was greater than the upper limit of normal (149 ng/ml). We derived the area under the curve (AUC) for the receiver operating characteristic curve (ROC) for all biomarkers.Between 31 August 2010 and 17 November 2010, we enrolled 92 patients; 17 of these patients had APACHE II diagnoses of sepsis. In patients with a diagnosis of sepsis, the predictive ability of all of the biomarkers measured was worse than in those without (Table Although the sample size is limited, there is a marked difference in the predictive ability of the measured biomarkers to predict AKI between septic and nonseptic patients. All patients admitted met the criteria for a diagnosis of SIRS, suggesting that inflammation and sepsis contribute to the development of AKI via different pathways. The ability of these biomarkers to predict AKI in patients with a diagnosis of sepsis in our cohort is limited. Further investigation is needed into whether the combination of specific biomarker patterns and clinical features can better identify patients at risk, particularly in the setting of sepsis. In addition, further work examining the relationship between the various biomarkers and the aetiology and natural history of AKI is required.


The goal of humankind is to alleviate the suffering from disease and quest is to have good and robust health always. The gain of knowledge through research is one of the primary steps towards the same. With the newly emerging infectious diseases, increase in the antimicrobial resistance and also the increasing incidences of noncommunicable diseases have thrown at us new challenges to develop better diagnostics, drugs, medical devices, and vaccines.The present century is the era of biotechnology and information technology. Biotechnology has become the amalgamation of several technologies ranging from the field of biomedical research and synthetic biology and further transcending to engineering, nanotechnology, and bioinformatics. Biomedicine have gone a step further converging biology, chemistry, and physics which have led to increasing the understanding of the pathophysiological processes by deciphering the molecular interaction that plays a significant role in the cellular mechanism and thus devising new strategies to produce new diagnostics and therapies.Health innovation process needs a boost to stem the declining productivity and high turnover rates of drugs with escalating cost. So, the promotion of newer technologies and innovation is the need of the hour. It is imperative to have health innovation reach the masses and add a value to the public health system of nations across the globe. With adequate impetus we are ushering in today the era of knowledge driven, evidence-based innovation in fields of biotechnology and biomedicine, leading to development of platform technologies which can have global implications.This special issue in the journal of Biomed Research is a step towards the path which brings us to the forefront of new innovations and technologies that transcend all aspects of translational research and have high significance in the public health arena. Hence the editors have selected the cutting edge research in the field of medical biology which has bearing in the future of science.The paper by Y. Qin et al., which have found that DNA vaccine encoding BCR/ABL-hil2 enhances the in vivo humoral and cellular responses in BABL/c mice, hence presenting a new targeted immunotherapy approach which holds promising finding for patients with chronic myeloid leukemia (CML). The paper postulates these findings and if the research is translated to effective DNA vaccine in humans for CML patients, it will help in the treatment of residual disease after the treatment with chemotherapy or targeted therapy.Persea americana var. drymifolia). This paper reports the antimicrobial activity of defensin from avocado against Escherichia coli and Staphylococcus aureus. The alternative method of pathogen control paves the way for development of new treatment regimes against infectious pathogens.New research in antimicrobial therapy has become a very essential tool to fight infection in context of growing antibiotic resistance. The paper by J. J. G.-R. Rodríguez et al., has given alternate strategy with cloned antimicrobial peptide PaDef homologous to defensins from Mexican avocado ( Curcuma longa L. (from the family Zingiberaceae) on fighting oxidative stress in liver and brain in mice fed with excessive alcohol was studied in the paper by C. W. Pyun et al. The finding showed that curcumin increases brain and hepatic phosphatidylcholine hydroperoxide levels in mice after consumption of excessive alcohol, hence proving the effectiveness of consumption of daily curcumin intake in protecting the liver and brain against alcohol induced oxidative stress.The effect of curcumin fromThe G. C. Fontes et al., paper on characterization of alginate and OSA starch bead for the use of controlled release carrier for penicillin is an important finding to alleviate the discomfort of patients undergoing conventional administration of the vital drug. This paper also has long implications on designing public health intervention for delivery of essential drugs.The paper by M. P. L. Cunha et al., is the analysis of the vaccine adverse event reporting in the state of Rondonia, Brazil during the first ten years (1998–2008) after introduction of vaccines for BCG , DTwP/Hib , DTP , MMR  and yellow fever (YF) is a major impact paper on public health. This study is of paramount importance which can help the regulators and clinicians alike from all over the world in gauzing the effectiveness and adverse reaction that can be anticipated from the regular vaccines that are a part of immunization programs of many countries around the world.The simple model to analyze assessment of the antitoxin antibodies in the paper by A. Skvortsov and P. Gray also is an essential scientific finding which was once validated experimentally will be a very useful tool to assess in vitro the potential of protective antibodies for further evaluation in vivo.The compilation of the articles in the special issue is very good read of high impact research and important scientific findings would have robust impact on strategizing innovative solutions of public health interventions globally; hence, all editors have selected the most promising research for publication.Nirmal K. GangulySimon CroftLalji SinghSubrata SinhaTanjore Balganesh


The collective behavior of a neuronal population can often be illuminated by representing neurons as simple phase oscillators, where the response of each neuron to its synaptic input is given by an infinitesimal phase response curve (iPRC). This approach can, for example, predict whether neuronal activity will tend to synchronize across the population depending on the nature of the synaptic coupling and the shape of the iPRCs-3. Despi


The overall network is obtained by joining all the neighborhoods. RegnANN makes no assumptions about the nature of the relationships between the variables, potentially capturing high-order and non linear dependencies between expression patterns. The evaluation focuses on synthetic data mimicking plausible submodules of larger networks and on biological data consisting of submodules of Escherichia coli. We consider Barabasi and Erdös-Rényi topologies together with two methods for data generation. We verify the effect of factors such as network size and amount of data to the accuracy of the inference algorithm. The accuracy scores obtained with RegnANN is methodically compared with the performance of three reference algorithms: ARACNE, CLR and KELLER. Our evaluation indicates that RegnANN compares favorably with the inference methods tested. The robustness of RegnANN, its ability to discover second order correlations and the agreement between results obtained with this new methods on both synthetic and biological data are promising and they stimulate its application to a wider range of problems.RegnANN is a novel method for reverse engineering gene networks based on an ensemble of multilayer perceptrons. The algorithm builds a regressor for each gene in the network, estimating its  The task of gene regulatory network (GRN) inference is a daunting task not only in terms of devising an effective algorithm, but also in terms of quantitatively interpreting the obtained results co-expression networks. On the basis that correlation coefficients fail to capture more complex statistical dependencies among expression patterns (e.g. non-linearity), more recently general methods based on measures of dependency such as mutual information have been proposed Early network inference models were based on the analysis of the correlation coefficients Escherichia coli), controlled by hundreds of regulators (e.g. approximately Escherichia coli), are recorded for a limited amount of experimental conditions - about 450 for the last publicly available Escherichia coli gene expression data set. Thus, considering also possible combinatorial regulations and feedback loops, the number of possible solutions of the inference problem becomes prohibitively large compared to the available experimental measurements at hand.One of the aspects that makes network inference a daunting task is its intrinsic underdetermination neighborhood of each gene  independently and then it joins these neighborhoods to form the overall network. RegnANN performance is compared with those of top-scoring methods such as KELLER In this work we introduce a novel inference method called Reverse Engineering Gene Networks with Artificial Neural Networks (RegnANN). This inference algorithm, trained using steady state data as provided by microarray data, builds a multi-variable regressor (one to many) for each gene in the network. The algorithm is based on an ensemble of Multilayer Perceptrons (MLPs) trained using steady state data. RegnANN estimates the Escherichia coli.In evaluating the performance of the four different network inference methods, first we settle in a controlled situation with synthetic data and then we focus on a biological setup by analyzing transcriptional subnetworks of The general performance of the network inference task is evaluated in terms of Matthews Correlation Coefficient - MCC The experimental evaluation firstly verifies RegnANN ability of inferring direct and indirect interactions among genes and possible cooperative interaction between putative regulators on a set of toy experiments. Considering only the underlying topology (e.g.: undirected unweighted graph), we then focus on synthetic data mimicking plausible submodules of larger networks generated according to both Barabasi Escherichia coli including a number of genes ranging from We finally demonstrate our approach on a biological data set consisting of a selected number of subnetworks of In order to present coherently the results obtained on synthetic data, we start firstly with an evaluation of RegnANN ability of inferring direct and indirect interactions among genes and possible cooperative interaction between putative regulators (e.g.: transcription factors). This is done on four toy examples considering interaction among four genes.The second phase of our analysis focuses on the effect of varying the amount of available data in the task of network inference while considering a fixed threshold for the binarization of the inferred adjacency matrix. The performance in terms of MCC obtained with RegnANN is systematically compared with the ones obtained by KELLER. The accuracy of each inference method is firstly evaluated on synthetic data by varying the topology of the network, the amount of data available and the method adopted to synthesize the data. Once the topology of the network is (randomly) selected, the desired amount of data is synthesized according to the generation method of choice, the network inference methods are applied and the MCC score calculated. We consider discrete  symmetric adjacency matrices for fair comparison between the two methods as KELLER does not infer coupling direction, nor the strength of the interaction. To account for intrinsic instability of each inference method, data generation and network inference are repeated The third phase of the experimental evaluation on synthetic data compares the performance of RegnANN, ARACNE and CLR in terms of AUC (the area under the curve). The curve is constructed by varying the value of the binarization threshold between Finally, we compare the results obtained on a selection of Escherichia coli gene subnetworks for the four inference algorithms. We will first start considering a fixed threshold for the binarization of the inferred adjacency matrix. Secondly, we briefly analyze the problem of optimal threshold selection for the binarization of the inferred adjacency matrix in the hypothesis of the presence of gold standard data, which is not available in most realistic biological applications. As for the two phases before, we consider discrete symmetric adjacency matrices.In this section we present four different toy experiments to illustrate how RegnANN is capable of inferring direct and indirect interactions among genes and cooperative interaction between putative regulators (e.g.: transcription factors).Let us consider four different genes The correlation matrix shown in Let us consider four different genes seed expressions with values uniformly distributed in We synthesize expression profiles very similarly to the SLC method: we start considering a set of The correlation matrix shown in Let us consider again the four different genes seed expressions with values uniformly distributed in  for each gene As in the previous case, we generate the gene expression profiles considering a set of The correlation matrix in As a final example, let us consider the four different genes seed expressions with values uniformly distributed in We generate the gene expression profiles considering a set of The correlation matrix in Strictly considering the adjacency matrix in In order to eliminate the ambiguity in the determination of the direction of the interaction among genes, in the following we will consider symmetric adjacency matrices as input for data generation and as the output of the network inference task. As a second possible solution, in the case of RegnANN we could have selected the direction of interaction by identifying the highest correlation value. On the other hand, this choice would have resulted in an unfair comparison with (i.e.) KELLER: the latter discards any information about the direction of the interaction. However, it is important to consider that an exhaustive analysis of the direction of the coupling would require a dedicated procedure to account for the variability of the regression.In this section we analyze the performance of RegnANN in inferring network topology by applying a fixed discretization threshold of data ratio: the ratio of the number of expression profiles to the number of nodes. We rescale linearly the synthetic gene expression values in In the following we show results obtained by varying the mean degree of the nodes between In the case of Erdös-Rényi topology with mean degree equal to In the case of Barabasi topology, the accuracy of both methods drops quickly to a value of It is interesting to note that for both topologies, KELLER tends to outperform RegnANN for mean degree values bigger and equal to In microarray experiments, the analysis of the raw data is often hampered by a number of technical and statistical problems. The possible remedies usually lie in appropriate preprocessing steps, proper normalization of the data and application of statistical testing procedures in the derivation of differentially expressed genes In this section we compare the performance of ARACNE, CLR and RegnANN varying the threshold applied to discretize the inferred adjacency matrix in terms of the the AUC (area under the curve) value.The figure indicates that the mean performance  or it should be derived from a gold standard data, which is not available in most realistic biological applications. An obvious solution to this problem is to adopt a training/validation schema: ground-truth data is used to infer the optimal threshold value while external data is used to verify the reconstruction accuracy. Here, for each module in Escherichia coli submodules as in The table indicates that the optimal threshold value depends on the algorithm adopted and the submodule considered.Escherichia coli submodule. Although outside the scope of this work, this preliminary evaluation indicates that in the case of biological data, learning the optimal threshold value via standard machine leaning methods is not straightforward: presence of noise in the data and the high complexity of the domain often cause selection bias. This is the key point that lead us focus on estimating the structures of the interaction between genes rather than the detailed strength of these interactions.In this work we presented a novel method for network inference based on an ensemble of multi-layer perceptrons configured as multi-variable regressor (RegnANN). We compared its performance to the performance of three different network inference algorithms  on the task of reverse engineering the gene network topology, in terms of the associated MCC score. The proposed method makes no assumptions about the nature of the relationships between the variables, capturing high-order dependencies between expression patterns and the direction of the interaction, as shown on selected synthetic toy examples. Our extensive evaluation indicates that the newly introduced RegnANN shows accuracy and stability scores that compare very favorably with all the other inference methods tested, often outperforming the reference algorithm in the case of fixed binarization threshold. On the other hand, considering all the possible thresholds for the binarization of the inferred adjacenci matrix (the AUC score) the differences among the tested methods tend to become irrelevant. Our evaluation on synthetic data demonstrates that various factors influence the performance of the inference algorithms adopted: the topology of network, its size and its complexity, the amount of data available, the normalization procedure adopted. Generally, these are only a few of the factors that may influence the outcome of a network inference algorithm; they may not be limited to the relative small set of parameters explored here.Escherichia coli, although the very same expression values are used to infer the different gene sub-networks. Our experiments indicate great variability of the scores of the reference inference algorithms across the different Escherichia coli sub-modules. On the other hand, RegnANN scores are more homogeneous, decreasing as the density of the module decreases.Results on the biological data confirm that the correctness of the inferred network depends on the topological properties of the modules: very different accuracy results are obtained on the different submodules of Finally, we tested the possibility of applying standard machine leaning methods to learn the optimal binarization threshold value. Our preliminary evaluation indicates that this is not a straightforward task: presence of noise in the data and the high complexity of the biological domain often cause selection bias.The robustness of RegnANN performance recorded across the board and the agreement between results obtained with this new methods on both synthetic and biological data are promising and they stimulate its application to a wider range of problems.neighborhood of each gene  independently and then joining these neighborhoods to form the overall network, thus reducing the problem to a set of identical atomic optimizations.To infer gene regulatory networks we adopt an ensemble of feed-forward multilayer perceptrons. Each member of the ensemble is essentially a multi-variable regressor (one to many) trained using an input expression matrix to learn the relationships (correlations) among a target gene and all the other genes. Formally, let us consider the multilayer perceptron as in n matrix . By cyclWe build The algorithm of choice for training each multi-layer perceptron is the back-propagation algorithm Although back-propagation is essentially a heuristic optimization method and alternatives such as Bayesian neural network learning The learning parameters we use to train each multi-layer perceptron are as follows: learning rate equal to Once the ensemble is trained, the topology of the gene regulatory network is obtained by applying a second procedure. Considering each gene in the network separately, we pass a value of http://sourceforge.net/projects/regnann/files/. The source code is distributed according to the GPLv3 license (open-source).To improve the general efficiency of the algorithm and thus to allow a systematic comparison of its performance with the other gene network reverse engineering methods tested, we implemented the ANN based regression system using the GPGPU programming paradigm. A reference implementation of the RegnANN algorithm is available at As reference methods we select three alternative algorithms widely used in literature: ARACNE, CLR and KELLER.KELLER is a kernel-reweighted logistic regression method With respect to other inference methodologies, KELLER adopt a fixed threshold to discretize the inferred adjacency matrix while it performs an optimization of the regularization weight lambda controlling the sparsity of the solution by maximizing a Bayesian Information Criterion (BIC). The authors apply a grid search on a selection of possible parameter values. In our work, we adopt the very same procedure: we use the same fixed discretization threshold for the binarization of the adjacency matrix, while we select the optimal solution by maximizing the BIC via a grid search for the optimal value of lambda  as performance metric.CLR is an extension of the relevance networks class of algorithms true positives, while FN indicates the fraction of false negatives.When the performance of a network inference method is evaluated, it is common practice to adopt two metrics: precision and recall. Recall indicates the fraction of true interactions correctly inferred by the algorithm, and it is estimated according to the following equation:false positives.On the other hand, precision measures the fraction of true interactions among all inferred ones, and it is computed as:In this work we adopt the Matthews Correlation Coefficients - MCC The MCC is in essence a correlation coefficient between the observed and predicted binary classifications: it returns a value between The Matthews Correlation Coefficient is calculated as:We benchmark the reverse engineering algorithms here considered using both synthetic and biological data.igraph extension package to the GNU R project for Statistical Computing The synthetic data sets are obtained starting from an adjacency matrix describing the desired topology of the network. Here we consider two different network topologies: Barabasi-Albert Once the topology of the network is (randomly) generated, the output profiles of each node are generated according to two different approaches: the first one considers only linear correlation among selected genes (SLC), the second one is based on a gene network/expression simulator recently proposed to assess reverse engineering algorithms GES . In ordeSimple Linear Correlation (SLC): similarly to the simulation of gene expression data presented in the supplementary material of seed expressions : this second methodology is based on a gene network simulator recently proposed to assess reverse engineering algorithms Escherichia coli starting from a set of steady state gene expression data. The data are obtained from different sources and they consist of three different elements, namely the whole Escherichia coli transcriptional network, the set of the transcriptional subnetworks and the gene expression profiles to infer the subnetworks from. The Escherichia coli transcriptional network is extracted from the RegulonDB (http://regulondb.ccg.unam.mx/) database, version Escherichia coli Affymetrix Antisense2 microarray expression profiles for The task for the biological experiments is the inference of a few transcriptional subnetworks of the model organism A number of sources of noise can be introduced into the microarray measurements, e.g. during the stage of hybridization, digitization and normalization. Therefore, it is often preferred to consider only the qualitative level of gene expression rather than its actual value In this work we compute the discrete value of the expression for each of the Generally, when a scaling method is applied to the data, it is assumed that different sets of intensities differ by a constant global factor In this work we test two different data rescaling methods:linear rescaling: each gene expression column-vector is linearly rescaled between statistical normalization: each gene expression column-vector is rescaled such that its mean value is equal to We consider gene expression matrices of dimension In this section we show how the tuning parameters of RegnANN impact its performance on a selected testbed: Barabasi networks with 100 nodes and SLC data generation. Accuracy scores (MCC) are calculated as mean of The two set of figures indicate that the values for the learning parameters adopted in the evaluation of the performance of RegnANN (momentum = eps) on a sample testbed. The reference implementation of ARACNE provided by In this section we explore the influence of the tolerance parameter (We adopt the eps parameter, e.g.: considering network size eps value eps value eps value eps value eps parameter value to eps value eps value eps value eps value The figure indicates that for Barabasi networks no statistically relevant difference in the performance of ARACNE is recoded varying the The figure indicates that the value


Cancer is a disease of aging.With the aging of the population the management of cancer in the older person with chemotherapy is beoming increasingly common. This treatment may be safe and effective if some appropriate measures are taken, including, an assessment of the physiologic age of each patient, modification of doses according to the renal function, use of meyelopoietic growth factors prophylactically in presence of moderately toxic chemotherapy, and provision of an adequate caregiver. Cure, prolongation of survival, and symptom palliation are universal goals of medical treatment. Prolongation of active life expectancy should be added to the treatment goal of the older aged person. The management of cancer in the older aged person is an increasingly common problem. Cancer is a disease of aging.Is the person life expectancy going to be shortened by cancer?Is the patient’s life expectancy long enough that he or she will experience the complications of cancer?Is the patient able to tolerate antineoplastic treatment?What are the long term side effects of cancer treatment in the older person?Does the patient have adequate social support to undergo cancer treatment?The management of cancer in the older-aged person include some questions that are specfic of aging:We will address these questions using cytotoxic chemotherapy as a model. After an overview of aging and its assessment we will explore the pharmacologic changes of aging and the provisions to ameliorate the complications of chemotherapy.Aging implies a decline in life expectancy and stress-coping ability, increased prevalence of comorbidity, increased risk of functional dependence and of the need of social support.Aging has been defined as loss of entropy and fractality10Homeostasis is the ability of a system to restore basic conditions after stress imposed by environmental interactions. One may observe the dysregulation of a number of physiologic parameters, including blood pressure, insulin sensitivity, circulating levels of corticosteroid and cathecolamines. The so called “allostatic load” assesses the dysregulation of 12 different parameters and may estimate the physiologic age. Its clinical value so faris unestablished.Inflammatory markers and the length of leukocyte telomeres are promising laboratory tests, but at present have limited clinical use.Table 1.17The best validated instrument for the assessment of chronologic age is the Comprehensive Geriatric Assessment” (CGA), whose elements are illustrated in Dependence in one or more ADLs and the presence of one or more geriatric syndromes imply a marginal functional reserve associated with very limited tolerance of stress. These individuals can only survive thanks to a full time home caregiver, or to admission to an adult living facility. Dependence in one or more IADLs is associated increased risk of mortality,In addition to reduced life-expectancy and increased risk of treatment complicationsSome elements of the CGA may be utilized in models that predict the mortality and the risk of chemotherapy-related toxicity in older individuals.34Any discussion of the assessment of physiologic age should include frailty. This is constructed as a condition of critically reduced physiologic reserve so that a minimal stress may cause loss of independence and start a chain of events that lead to the patient ‘s death.3Involuntary weight loss of 10 lbs or more over a 6 months period;Decreased grip strength;Difficulty in starting movements;Reduced walk speed;Exhaustion.The clinical definition of frailty was first provided by the Cardiovascular Health Study (CHS).The three groups of individuals were classified as: non-frail or fit ; pre-frail , and frail .Another index of frailty validated both in older women and older men has been provided by the Study of Osteoporotic Fracture (SOF)The interactions of aging and frailty should be clarified. In particular we should ask: is cancer a cause of frailty? Is chemotherapy a cause of frailty? Is frailty associated with increased risk of therapeutic complications?Table 2).40Aging is associated with pharmacokinetic and pharmacodinamic changes that may enhance the toxicity of these agents  and in interrupting treatment when the neuropathy may interfere with an individual’s activity.An important and unanswered question is whether age is a risk factor for more frequent and more severe manifestations of “chemobrain” that is a cognitive dysfunction caused by chemotherapy.Age is a risk factor for delayed complications of chemotherapy. Myelodysplasia and acute myeloid leukemia may develop in 1–2% of patients 65 and over who had received anthracycline-containing treatment in the previous 10 years. The risk of these complications is enhanced by myelopoietic growth factors.49Other potential long term complications of cancer chemotherapy include dementia, functional dependence and frailty.Cure, prolongation of survival, and symptom palliation are universal goals of medical treatment. Prolongation of active life expectancy should be added to the treatment goal of the older aged person.The construct of active life expectancyWith the aging of the population the management of cancer in the older person with chemotherapy is beoming increasingly common. This treatment may be safe and effective if some appropriate measures are taken, including, an assessment of the physiologic age of each patient, modification of doses according to the renal function, use of meyelopoietic growth factors prophylactically in presence of moderately toxic chemotherapy, and provision of an adequate caregiver. The goals of treatment should include prolongation of active life-expectancy.


Perinatal infections include pregnancy associated infections, fetus infection during labor, and other types of infections, including the early postnatal and late postnatal ones that appeared in the range of one month after birth. They represent a constant threat to the health of the conceptus, fetus and newborn. Therefore their early diagnosis is fundamental in terms of establishing a fair treatment of maternal infection for prophylaxis of product conception and fetal illness and treatment of neonatal infections.Starting from current practice realities, the authors show the need to include infectious disease specialist consultants in all periods: in antepartum, during the first trimester and occasionally in the remainder of the pregnancy and postpartum. In this way it is possible to avoid the excess diagnosis of potentially teratogenic acute infections included in the acronym TORCH during pregnancy.


Seismic design loads for tunnels are characterized in terms of the deformations imposed on the structure by surrounding ground. The free-field ground deformations due to a seismic event are estimated, and the tunnel is designed to accommodate these deformations. Vertically propagating shear waves are the predominant form of earthquake loading that causes the ovaling deformations of circular tunnels to develop, resulting in a distortion of the cross sectional shape of the tunnel lining. In this paper, seismic behavior of circular tunnels has been investigated due to propagation of shear waves in the vertical direction using quasi-static analytical approaches as well as numerical methods. Analytical approaches are based on the closed-form solutions which compute the forces in the lining due to equivalent static ovaling deformations, while the numerical method carries out dynamic, nonlinear soil-structure interaction analysis. Based on comparisons made, the accuracy and reliability of the analytical solutions are evaluated and discussed. The results show that the axial forces determined using the analytical approaches are in acceptable agreement with numerical analysis results, while the computed bending moments are less comparable and show significant discrepancies. The differences between the analytical approaches are also investigated and addressed. Underground structures do not fall in resonance with the ground, however, response in accordance with the response of the surrounding ground. Therefore, seismic design loads for underground structures are generally characterized in terms of the deformations imposed on the structure by the surrounding ground. The free-field ground deformations due to a seismic event are estimated, and the tunnel is designed to accommodate these deformations. Underground structures are assumed to experience three primary modes of deformation during seismic shaking :axial coAxial deformations in tunnels are generated by the components of the seismic waves that produce motions parallel to the axis of the tunnel and cause alternating compression and tension. Bending deformations are caused by the components of seismic waves producing particle motions perpendicular to the longitudinal axis. Design considerations for axial and bending deformations are generally in the direction along the tunnel axis . Ovalingfree-field deformation approach;soil-structure interaction approach.Studies have suggested that, while ovaling may be caused by waves propagating horizontally or obliquely, vertically propagating shear waves are the predominant form of earthquake loading that causes these types of deformations . There aIn this paper, seismic behavior of circular tunnels has been investigated due to propagation of shear waves in the vertical direction using quasi-static analytical approaches as well as numerical methods. This issue has been investigated in the past by several researchers using numerical and analytical methods, which has led to solutions and results. In particular, analytical solutions are still very popular, as confirmed by the growing body of the literature devoted to this topic: while early studies referred to simplified geometries  and constitutive assumptions , recently proposed closed-form solutions deal, as an example, with piecewise tunnel lining connected by joints , nonunifThe surrounding soil of the tunnels constructed in the urban areas, usually consisting of the alluvium and low strength soil, experiences large deformation during ground motions. In this case the soil is voided elastic state and undergoes large plastic deformation. One of the best methods for modeling large deformations is finite difference method. The use of structural elements available in FLAC allows the dynamic soil-structure interaction analysis to be performed. In this research the nonlinear finite difference method has been used, which allows the dependence of damping and stiffness of the material to the strain level to be considered and taken into account. Also, the shallow circular tunnels under the propagation of shear waves have been analyzed to compare the analytical solutions with the numerical finite difference method. The geotechnical properties of the materials used in the analyses are obtained from the geotechnical investigations performed for the second line of Tabriz urban subway project (Iran). Also the input variables such as the maximum shear strain at tunnel's level, the shear modulus proportional to the level of the strain, and the maximum particle velocity of the mass required in the analyses with the analytical methods are determined using two-dimensional free-field numerical analysis.In order to make use of actual data, the cross sections and their material properties chosen for the analyses are obtained from the geotechnical reports prepared for Tabriz subway project. The properties have been used from the geotechnical reports including the reports of geophysics vibration tests to determine the elastic properties for dynamic analysis and the goal of these tests is measuring the velocity of volume and shear waves in cross sections to determine the dynamic properties of the soil. The data and specifications of Sections 1 and 2 used in the analyses are shown in Also shown in determination of the backbone (skeleton) curve;application of a set of rules relevant to behavior of loading and unloading and reduction of stiffness along with other required parameters.The numerical analyses were performed with the code FLAC  which alCs is the minimum velocity of the shear wave and Δl is the largest dimension of element. For each cross section the maximum frequency is determined and, by use of the code filtration function, the higher frequencies are deleted from the ground motion data.By defining the hysteretic model for dynamic analysis, the modulus reduction curve of the material is determined as a skeleton curve for conducting nonlinear analysis. For dynamic analysis, the elements dimensions are limited by the criterion of wave transmission. The dimension of the largest element and the minimum velocity of the shear wave are used to determine the maximum value of the frequency as follows:ρ is the density, σs is the applied shear stress, Cs is propagation velocity of the shear wave, and vs is shear particle velocity.The lateral boundaries of the model must take into account the free-field conditions. In order to minimize the reflection of waves from bottom boundary of the model, the boundary is considered as quite boundary, and consequently the seismic input should be defined as a stress wave. By integrating the acceleration time history, the velocity time history is determined and the input wave is subsequently changed into the stress shear wave using the following relationship:The acceleration of the top and bottom joints is also compared with the maximum input acceleration, and if needed the applied coefficient can be corrected in such a way that the modified acceleration approximates the exact value. The hysteretic damping is used to attenuate the energy of the numerical modeling. The modulus reduction curves proposed by Sun et al.  for fineMs is secant modulus, γ is the shear strain, and L1 and L2 are bounds of the logarithmic strain (points at which gradients are zero). Figures in which Vertically propagating shear waves are the predominant form of earthquake loading that causes the ovaling deformations of circular tunnels to develop, resulting in a distortion of the cross sectional shape of the tunnel lining. The most important and useful analytical methods for calculating these deformations are Wang and Penzien methods , 19 and Wang and Penzien solutions are developed for both full-slip and no-slip condition between the tunnel and lining. As the structural elements are directly joint to the surrounding soil, the no-slip condition is used in this paper. The input parameters in Wang and Penzien methods are cover's geometric and elastic properties, elastic properties of soil mass, and the maximum shear strain caused by the ground motions. The basic point in Wang and Penzien methods is determining the shear modulus. The shear modulus of soil materials is dependent on the level of shear strain and on higher shear strain levels; the maximum shear modulus determined by the geophysical tests will be decreased. The results obtained by use of the maximum shear modulus are therefore overestimated, and consequently the compatible shear modulus should be used. The shear modulus and shear strain parameters are determined by numerical modeling of the free-field condition. Figures Bobet  presenteBobet presented the solution by assuming the no-slip condition between the tunnel and the lining at dry and saturated conditions. In this study, both conditions have been considered and investigated. The maximum particle velocity at the tunnel axis is obtained by the free-field numerical modeling. In numerical models, the tunnel cover has been shown with 72 structural elements which are rigidly connected to each other. The number of the elements is governed by the size of the surrounding zones, and therefore, in order to increase the accuracy, one structural element is created in each surrounding zone of the excavated tunnel. Dynamic loading is used in the models which are in statically stable conditions. By considering excavating conditions, the numerical models are first reached to the static equilibrium and then the dynamic analysis can be started. The numerical model of cross section 1 has been shown in In this research, 8 structural elements have been chosen for each cross section in order to record the force and moment time histories during dynamic loading. The results of the numerical analyses are obtained by determining the moment and force time histories during model seismic motions along with their maximum values. In the stable condition, before applying dynamic input, values of these parameters detracted from the maximum values during the dynamic wave passage, in order to determine the net maximum values. Owing to the generation of numerous time history curves and for the sake of space saving, only two history curves for each of axial and shear forces as well as bending moments related to two points of the above-mentioned eight structural element points at various positions are provided. Figures In this section, forces imposed on tunnel lining after seismic loading are investigated. Also, results of the finite difference numerical method are compared with the results obtained by Wang-Penzien and Bobet analytical methods in the no-slip condition. One maximum value for axial force is determined by Wang and Penzien methods. Also for seismic ground motions induced by shear waves, one maximum value is obtained for axial force by Bobet method. As shown in Figures The bending moment of analytical and numerical methods is compared in Figures As shown in Figures Underground structures using numerical methods are necessary because of many complicated conditions such as heterogeneous layers, irregular geometry of tunnels, ground water, and soil-structure interactions. The results of numerical methods should be compared with analytical methods. The maximum values of axial forces obtained by numerical analyses are more than the other three analytical methods because of reduction coefficient of shear modulus. The results of analytical methods seemed to be overestimated, since the maximum values of shear modulus have been used.The result obtained by Bobet method in dry ground is the closest one to the results of numerical analysis in both cross sections. Also the axial forces computed by Bobet method in dry and saturated ground are approximately the same. By assuming saturated condition in Bobet method, the axial forces induced by shear waves are a little less than the axial force obtained in the dry ground. The axial forces computed by Wang method are close to the results of Bobet method. The solutions of Penzien  result iIn the case of bending moment, the highest value was obtained by the numerical modeling. The results of four analytical methods are very close to each other, and the results of Penzien method are compatible with the others. However, the differences with the results of numerical modeling are noticeable and Tables