Retrograde semaphorin-plexin signalling drives homeostatic synaptic plasticity.

Homeostatic signalling systems ensure stable but flexible neural activity and animal behaviour. Presynaptic homeostatic plasticity is a conserved form of neuronal homeostatic signalling that is observed in organisms ranging from Drosophila to human. Defining the underlying molecular mechanisms of neuronal homeostatic signalling will be essential in order to establish clear connections to the causes and progression of neurological disease. During neural development, semaphorin-plexin signalling instructs axon guidance and neuronal morphogenesis. However, semaphorins and plexins are also expressed in the adult brain. Here we show that semaphorin 2b (Sema2b) is a target-derived signal that acts upon presynaptic plexin B (PlexB) receptors to mediate the retrograde, homeostatic control of presynaptic neurotransmitter release at the neuromuscular junction in Drosophila. Further, we show that Sema2b-PlexB signalling regulates presynaptic homeostatic plasticity through the cytoplasmic protein Mical and the oxoreductase-dependent control of presynaptic actin. We propose that semaphorin-plexin signalling is an essential platform for the stabilization of synaptic transmission throughout the developing and mature nervous system. These findings may be relevant to the aetiology and treatment of diverse neurological and psychiatric diseases that are characterized by altered or inappropriate neural function and behaviour

The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

The variability and seasonality of the environmental reservoir of Mycobacterium bovis shed by wild European badgers

This is the final version of the article. Available from the publisher via the DOI in this record.The incidence of Mycobacterium bovis, the causative agent of bovine tuberculosis, has been increasing in UK cattle herds resulting in substantial economic losses. The European badger (Meles meles) is implicated as a wildlife reservoir of infection. One likely route of transmission to cattle is through exposure to infected badger urine and faeces. The relative importance of the environment in transmission remains unknown, in part due to the lack of information on the distribution and magnitude of environmental reservoirs. Here we identify potential infection hotspots in the badger population and quantify the heterogeneity in bacterial load; with infected badgers shedding between 1 × 10(3)- 4 × 10(5) M. bovis cells g(-1) of faeces, creating a substantial and seasonally variable environmental reservoir. Our findings highlight the potential importance of monitoring environmental reservoirs of M. bovis which may constitute a component of disease spread that is currently overlooked and yet may be responsible for a proportion of transmission amongst badgers and onwards to cattle.We acknowledge funding from Defra, H.C.K. was in receipt of a BBSRC DTG studentship and E.M.W. and O.C. acknowledge support from BBSRC for collaboration with Eamonn Gormley, UCD. We are also grateful to the APHA field team at Woodchester Park for support during fieldwork, and to Defra who fund the long-term stud

Image Tracking Study on Courtship Behavior of Drosophila

Background: In recent years, there have been extensive studies aimed at decoding the DNA. Identifying the genetic cause of specific changes in a simple organism like Drosophila may help scientists recognize how multiple gene interactions may make some people more susceptible to heart disease or cancer. Investigators have devised experiments to observe changes in the gene networks in mutant Drosophila that responds differently to light, or have lower or higher locomotor activity. However, these studies focused on the behavior of the individual fly or on pair-wise interactions in the study of aggression or courtship. The behavior of these activities has been captured on film and inspected by a well-trained researcher after repeatedly watching the recorded film. Some studies also focused on ways to reduce the inspection time and increase the accuracy of the behavior experiment. Methodology: In this study, the behavior of drosophila during courtship was analyzed automatically by machine vision. We investigated the position and behavior discrimination during courtship using the captured images. Identification of the characteristics of drosophila, including sex, size, heading direction, and wing angles, can be computed using image analysis techniques that employ the Gaussian mixture model. The behavior of multiple drosophilae can also be analyzed simultaneously using the motion-prediction model and the variation constraint of heading direction. Conclusions: The overlapped fruit flies can be identified based on the relationship between body centers. Moreover, th

Ratios of involved nodes in early breast cancer

INTRODUCTION: The number of lymph nodes found to be involved in an axillary dissection is among the most powerful prognostic factors in breast cancer, but it is confounded by the number of lymph nodes that have been examined. We investigate an idea that has surfaced recently in the literature (since 1999), namely that the proportion of node-positive lymph nodes (or a function thereof) is a much better predictor of survival than the number of excised and node-positive lymph nodes, alone or together. METHODS: The data were abstracted from 83,686 cases registered in the Surveillance, Epidemiology, and End Results (SEER) program of women diagnosed with nonmetastatic T1–T2 primary breast carcinoma between 1988 and 1997, in whom axillary node dissection was performed. The end-point was death from breast cancer. Cox models based on different expressions of nodal involvement were compared using the Nagelkerke R(2 )index (R(2)(N)). Ratios were modeled as percentage and as log odds of involved nodes. Log odds were estimated in a way that avoids singularities (zero values) by using the empirical logistic transform. RESULTS: In node-negative cases both the number of nodes excised and the log odds were significant, with hazard ratios of 0.991 (95% confidence interval 0.986–0.997) and 1.150 (1.058–1.249), respectively, but without improving R(2)(N). In node-positive cases the hazard ratios were 1.003–1.088 for the number of involved nodes, 0.966–1.005 for the number of excised nodes, 1.015–1.017 for the percentage, and 1.344–1.381 for the log odds. R(2)(N )improved from 0.067 (no nodal covariate) to 0.102 (models based on counts only) and to 0.108 (models based on ratios). DISCUSSION: Ratios are simple optimal predictors, in that they provide at least the same prognostic value as the more traditional staging based on counting of involved nodes, without replacing them with a needlessly complicated alternative. They can be viewed as a per patient standardization in which the number of involved nodes is standardized to the number of nodes excised. In an extension to the study, ratios were validated in a comparison with categorized staging measures using blinded data from the San Jose–Monterey cancer registry. A ratio based prognostic index was also derived. It improved the Nottingham Prognostic Index without compromising on simplicity

On renormalization group flows and the a-theorem in 6d

We study the extension of the approach to the a-theorem of Komargodski and Schwimmer to quantum field theories in d=6 spacetime dimensions. The dilaton effective action is obtained up to 6th order in derivatives. The anomaly flow a_UV - a_IR is the coefficient of the 6-derivative Euler anomaly term in this action. It then appears at order p^6 in the low energy limit of n-point scattering amplitudes of the dilaton for n > 3. The detailed structure with the correct anomaly coefficient is confirmed by direct calculation in two examples: (i) the case of explicitly broken conformal symmetry is illustrated by the free massive scalar field, and (ii) the case of spontaneously broken conformal symmetry is demonstrated by the (2,0) theory on the Coulomb branch. In the latter example, the dilaton is a dynamical field so 4-derivative terms in the action also affect n-point amplitudes at order p^6. The calculation in the (2,0) theory is done by analyzing an M5-brane probe in AdS_7 x S^4. Given the confirmation in two distinct models, we attempt to use dispersion relations to prove that the anomaly flow is positive in general. Unfortunately the 4-point matrix element of the Euler anomaly is proportional to stu and vanishes for forward scattering. Thus the optical theorem cannot be applied to show positivity. Instead the anomaly flow is given by a dispersion sum rule in which the integrand does not have definite sign. It may be possible to base a proof of the a-theorem on the analyticity and unitarity properties of the 6-point function, but our preliminary study reveals some difficulties.Comment: 41 pages, 5 figure

Emotion based attentional priority for storage in visual short-term memory

A plethora of research demonstrates that the processing of emotional faces is prioritised over non-emotive stimuli when cognitive resources are limited (this is known as ‘emotional superiority’). However, there is debate as to whether competition for processing resources results in emotional superiority per se, or more specifically, threat superiority. Therefore, to investigate prioritisation of emotional stimuli for storage in visual short-term memory (VSTM), we devised an original VSTM report procedure using schematic (angry, happy, neutral) faces in which processing competition was manipulated. In Experiment 1, display exposure time was manipulated to create competition between stimuli. Participants (n = 20) had to recall a probed stimulus from a set size of four under high (150 ms array exposure duration) and low (400 ms array exposure duration) perceptual processing competition. For the high competition condition (i.e. 150 ms exposure), results revealed an emotional superiority effect per se. In Experiment 2 (n = 20), we increased competition by manipulating set size (three versus five stimuli), whilst maintaining a constrained array exposure duration of 150 ms. Here, for the five-stimulus set size (i.e. maximal competition) only threat superiority emerged. These findings demonstrate attentional prioritisation for storage in VSTM for emotional faces. We argue that task demands modulated the availability of processing resources and consequently the relative magnitude of the emotional/threat superiority effect, with only threatening stimuli prioritised for storage in VSTM under more demanding processing conditions. Our results are discussed in light of models and theories of visual selection, and not only combine the two strands of research (i.e. visual selection and emotion), but highlight a critical factor in the processing of emotional stimuli is availability of processing resources, which is further constrained by task demands

Germline polymorphisms as modulators of cancer phenotypes

Identifying the complete repertoire of genes and genetic variants that regulate the pathogenesis and progression of human disease is a central goal of post-genomic biomedical research. In cancer, recent studies have shown that genome-wide association studies can be successfully used to identify germline polymorphisms associated with an individual's susceptibility to malignancy. In parallel to these reports, substantial work has also shown that patterns of somatic alterations in human tumors can be successfully employed to predict disease prognosis and treatment response. A paper by Van Ness et al. published this month in BMC Medicine reports the initial results of a multi-institutional consortium for multiple myeloma designed to evaluate the role of germline polymorphisms in influencing multiple myeloma clinical outcome. Applying a custom-designed single nucleotide polymorphism microarray to two separate patient cohorts, the investigators successfully identified specific combinations of germline polymorphisms significantly associated with early clinical relapse. These results raise the exciting possibility that besides somatically acquired alterations, germline genetic background may also exert an important influence on cancer patient prognosis and outcome. Future 'personalized medicine' strategies for cancer may thus require incorporating genomic information from both tumor cells and the non-malignant patient genome

Relationships between TGFβ Proteins and Oxygen Concentrations Inside the First Trimester Human Gestational Sac

In early pregnancy, the O2 gradient between the maternal circulation and the gestational sac tissues modulates trophoblast biological functions. The aim was to evaluate if placental partial pressure of oxygen (PaO2) modulates in vivo synthesis of specific placental proteins inside the first trimester gestational sac. Matched samples of peripheral venous blood, blood from the placental bed (PB), coelomic fluid (CF) and placental tissue were obtained in 37 normal pregnancies at 6–12 weeks gestation. PaO2 was measured in PB and CF using an IRMA blood gas monitor. Inhibin A, activin A, sEng, PlGF, sFlt-1 and free VEGF concentrations were measured in all samples. HSP 70 was measured in placental extracts. ANOVA showed ∼60% increase in PB PaO2 (P = 0.02) between after 10 weeks gestation. Unpaired Student's T-test between two groups (6–9 weeks vs 9–12 weeks) shows a significant increase in MS Activin A (P = 0.001), CF activin A (P<0.001), MS P1GF (P = 0.001), CF PlGF (P<0.001), MS sFLT-1 (P = 0.03), CF sFLT-1 (P = 0.01), HSP 70 in placental extracts (P = 0.04) and a significant decrease in PB inhibin A levels (P<0.001) and PB sFLT-1 (P = 0.02) . Multiple correlation analysis showed a significant negative correlation between PB inhibin A levels and gestation (r = −0.45, P<0.05) and PB PaO2 (r = −0.5, P = 0.008) and also between sFLT-1 and PB PaO2 (P = 0.03). There was a positive correlation (P<0.01) between PlGF, sEng and VEGF levels in the placental extracts. Our results indicate a direct relationship in the early intrauterine PaO2 in vivo and inhibin A and sFLT-1 concentrations confirming our hypothesis that specific placental proteins are regulated by intrauterine O2 tension