The pneumococcal alpha-glycerophosphate oxidase enhances nasopharyngeal colonization through binding to host glycoconjugates

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen, causing a broad spectrum of diseases including otitis media, pneumonia, bacteraemia and meningitis. Here we examined the role of a potential pneumococcal meningitis vaccine antigen, alpha-glycerophosphate oxidase (SpGlpO), in nasopharyngeal colonization. We found that serotype 4 and serotype 6A strains deficient in SpGlpO have significantly reduced capacity to colonize the nasopharynx of mice, and were significantly defective in adherence to human nasopharyngeal carcinoma cells in vitro. We also demonstrate that intranasal immunization with recombinant SpGlpO significantly protects mice against subsequent nasal colonization by wild type serotype 4 and serotype 6A strains. Furthermore, we show that SpGlpO binds strongly to lacto/neolacto/ganglio host glycan structures containing the GlcNAcβ1-3Galβ disaccharide, suggesting that SpGlpO enhances colonization of the nasopharynx through its binding to host glycoconjugates. We propose that SpGlpO is a promising vaccine candidate against pneumococcal carriage, and warrants inclusion in a multi-component protein vaccine formulation that can provide robust, serotype-independent protection against all forms of pneumococcal disease

Structural neuroimaging correlates of social deficits are similar in autism spectrum disorder and attention-deficit/hyperactivity disorder: analysis from the POND Network

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal–parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to \u3c0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders

Development and evaluation of prefabricated antipronation foot orthosis

Our aim was to develop and evaluate a new antipronation foot orthosis that addressed problems perceived by clinicians and users with existing foot orthoses. Clinicians and users were engaged to develop a user specification for the orthosis, and orthotic geometry and materials were developed using clinical reasoning. The orthotic material properties were tested and the ability of the orthosis to reduce foot pronation evaluated on 27 individuals. Clinicians expressed concern that current prefabricated orthoses often did not offer sufficient support to the foot because of a combination of the shape and materials used, and users concurred but also highlighted issues of durability and hygiene. The geometry of the new orthosis was, therefore, adjusted to enable individual foot size orthoses to be produced. A material was selected that was harder and more durable than materials used in many prefabricated orthoses. When the new orthosis was being worn, maximum rearfoot eversion was reduced in both walking (mean reduction 3.8 degrees, p < 0.001) and running (mean reduction 2.5 degrees, p < 0.001). Through a structured process, orthotic design decisions were made that addressed the specific concerns of clinicians and users and the new orthosis was proven to reduce rearfoot pronation

EIN ALTKROATISCHES GRABERFELD AUF DEM BERGE SPAS BEI KNIN

Autor objavljuje rezultate istraživanja starohrvatske nekropole na brdu Spasu kod Knina (otkriveno ukupno 228 grobova). Na temelju prikupljenih podataka tijekom višegodišnjih arheoloških istraživanja i sprovedene analize grobne arhitekture, pogrebnih običaja i grobnih nalaza utvrđeno je vrijeme ukopavanja na toj nekropoli i uputilo na mogući prostorni smještaj naselja kojemu je to groblje pripadalo. Završna razmatranja objelodanjenih grobnih nalaza otkrivaju niz novih spoznaja o gospoda.stvenim mogućnostima stanovništva, njihov kulturni i duhovni život u 9, 10. i 11. stoljeću. Osim starohrvatskih grobova na Spasu su otkopani i temeljni ostaci arhitekture, za koje se utvrdilo da pripadaju rimskom naselju, vjerojatno ostacima stare Ninie, odnosno Curcuma. Sve to popraćeno je obilnom dokumentacijskom građom i katalogom grobova.Westlich der Stadt Knin erstreckt sich der Berg Spas. Auf seinem siidlichen Teil erhebt sich die mittelalterliche Festung Knin, und an den nord lichen Teil schlieBt sich das Hochplateau des Berges Spas an, das im horizontalen Querschnitt cinE\u27 birnentormige Form hat. Spas ist anfangs des 18. lahrhunderts durch einen kiinstlichen Durchstich von der Festung getrennt worden. Im nordlichen, breitesten Teil des Plateaus wurde ein altkroatisches Graberfeld entdeckt, mit insgesamt 228 Grabern. Das erforsci1te Gebiet umfaBt etwa 1200 m2 Oberflache. Es wurden neben Grabern auch Fundamente von Bauwerken aus vorktoatischer Zeit gefunden, was bezeugt, daB es sich hier um eine komplexe archaologische Fundstatte handelt. Im ersten Teil seiner Abhandlung beschreibt. der Verfasser die Lage des Fundortes, seine strategische Bedeutung, und den geschichtlichen Ablauf der Forschungen an diesem Ort. AuBerdem erwahnt er unter anderen bedeutenden Funden auch die Entdeckung von Fundamenten von Bauwerken , fUr die er aufgrund von Fragmenten steinernen Skulpturen, Ziegeln und Fragmenten von KeramikgefaBen festelIen konnte, daB sie einer romisehen Ansiedlung angehorten. Durch Suchgrabung wurde festgestelIt, daB die Reste dieser Bauwerke sich auch auf den iibrigen Teil des Plateaus erstrecken, der bis jetzt nicht erforscht worden ist. Diese Entdeckungen, zusammen mit einem groBen, schon friiher untersuchten Graberfeld am ostlichen FuBe dieses Berges, genannt »Greblje«, sind ein starkes Argumentfi.ir die Annahme jener Forscher, die der Meinung sind, daB die alte, antike Stadtsiedlung Ninia, die von der Schriftstellern der Antike erwahnt wird , sich an der SteIle der heutigen Stadt Knin befunden hatte, beziehungsweise an der Stelle ihrer Festung und der Wallburg Spas. Im siidostlichen Teil des ausgegrabenen Graberfeldes hat man ziemlich groBe Schuttablagerungen gefunden, unter denen sich auch Stiicke von Mortel mit Farbresten befanden. An dieser Stelle und in ihrer unmittelbaren Nahe wurden einige steinerne Fragmente mit vorromanischer F1echtwerkplastik gefunden , die zu Kircheneinrichtungsgegenstanden aus dem 9. oder 10. lh. gehorten. Die erwahnten Funde weisen mjt Sicherheit darauf hin, daB sich an eben dieser Stelle, wo man den Schutt gefunden hat, eine altkroatische Kirche befunden hatte, der die gefundenen Fragmente angehorten. Da sich von diesem Kirchenbau auch nicht der allergeringste Rest einer Mauer erhalten hat, kann man nur schlieBen, daB die Kirche bis zu den Grundmauern zerstort worden war, und daB ihre Steine als Baurnaterial fUr die Mauern der nahegelegenen Festung verwendet wurden. Der zwei te Teil dieser Abhandlung enthalt den Katalog der Grabarchitektur und ihres lnventars. Hier findet man kurz gefaBt die wichtigsten Angaben i.iber jedes cinzeIne Grab und die osteologischen Funde, sowie eine genaue Beschreibung der Grabbeigaben. Der dritte Teil behandelt die allgemeinen Merkmale des Graberfeldes. Wegen der ungi.instigen Bodenstruktur, sowie der Fundamente der Bauwerke, besitzt das Graberfeld nicht die Merkmale von Reihengrabern, Die Graber sind sehr verschiedenartig orientiert, und liegen in allen Richtungen; der groBte Teil der Graber war trotzdem richtjg orientiert, in der Richtung Osten-Westen (103 Graber) . In den meisten Grabern befand sich nur ein Verstorbener, manchmal jedoch auch mehrere. Die gefundenen osteologischen Reste bestatigen, daB das Graberfeld einer Siedlung zugehorig; mit einer gleich groBen Anzahl von bestatteten Mannern , Frauern und Kindern. Die Graber waren meistens aus behauener Rauhwacke , aus unregelmaBigen Steinplatten oder aus Bruchsteinen gebaut. Die behauene Rauhwacke ftir die Graber stammte wahrscheinlich von den eingesttirzten Bauwerken in der nahen Umgebung. Weiterhin analysiert der Verfasser die Grabfunde, meistens Schmuck, und zwar Ohrringe und Ringe. Indem er die typologischen Besonderheiten der einzelnen Gegenstande genau beurteilt, und sie mit analogem Material aus den tibrigen altkroatischen und anderen Graberfeldern vergleicht, kommt er zu Schltissen ber die Herkunft und\u27 Datierung der Funde. Mehr Aufmerksamkeit schenkt der Verfasser den Ohrringen vom Typ mit drei Beeren und zwar deshalb, weil in letzter Zeit versucht wurde, fast alle entwickelteren Varianten dieses Typs, die in Grabern auf dem Gebiet des altkroatisches Staates gefunden worden waren, von allen tibrigen Ohrringen die ebenfalls auf diesem Gebiet gefunden wurden, zu trennen. [ndem er auf das Problem der Datierung und Herkunft der Ohrringe mit drei Beeren eingeht, versuchte der Verfasser aufgrund einer Reihe sicherer Tatsachen und Hinweise darauf hinzuweisen, daB dieser Typ von Ohrringen, beziehungsweise die starker entwickelten Varianten , nicht von den tibrigen Typenvarianten altkroatischer Ohrringe isoliert werden dtirfen, die auf dem Gebiet des dalmatinischen Kroatiens gefunden worden waren , und die meistens in die Zeit vom Beginn des 9. bis zum Ende des 11. lahrhunderts datiert werden. Er machte ebenfalls darauf aufmerksam, daB samtliche Typen von altkroatischen Ohrringen, und so auch die entwickelteren Varianten von Ohrringen mit drei Beeren, die aus Grabern des Mutterlandes stammen, aus einheimischen Goldschmiedewerkstatten stammen , und daB sie als Ganzes eine altkroatische Kulturgruppe bilden. AuBer seinen Vermutungen tiber die Lage und GroBe der Ansiedlung, zu der das Graberfeld auf dem Berge Spas gehorte, ist der Verfasser im Ganzen der Meinun~, daB das Graberfeld auf Spas dem Zeitraum des frtihfeudalen kroatischen Staates angehorte, d. h., daB das Graberfeld sei t dem Anfang des 9. Jahrhunderts bestanden hatte und kontinuierlich bis zum Ende des ll. Jahrhunderts fortdauerte

High-yield methods for accurate two-alternative visual psychophysics in head-fixed mice

Research in neuroscience increasingly relies on the mouse, a mammalian species that affords unparalleled genetic tractability and brain atlases. Here, we introduce high-yield methods for probing mouse visual decisions. Mice are head-fixed, facilitating repeatable visual stimulation, eye tracking, and brain access. They turn a steering wheel to make two alternative choices, forced or unforced. Learning is rapid thanks to intuitive coupling of stimuli to wheel position. The mouse decisions deliver high-quality psychometric curves for detection and discrimination and conform to the predictions of a simple probabilistic observer model. The task is readily paired with two-photon imaging of cortical activity. Optogenetic inactivation reveals that the task requires mice to use their visual cortex. Mice are motivated to perform the task by fluid reward or optogenetic stimulation of dopamine neurons. This stimulation elicits a larger number of trials and faster learning. These methods provide a platform to accurately probe mouse vision and its neural basis

‘Trial and error…’, ‘…happy patients’ and ‘…an old toy in the cupboard’: a qualitative investigation of factors that influence practitioners in their prescription of foot orthoses

Background: Foot orthoses are used to manage of a plethora of lower limb conditions. However, whilst the theoretical foundations might be relatively consistent, actual practices and therefore the experience of patients is likely to be less so. The factors that affect the prescription decisions that practitioners make about individual patients is unknown and hence the way in which clinical experience interacts with knowledge from training is not understood. Further, other influences on orthotic practice may include the adoption (or not) of technology. Hence the aim of this study was to explore, for the first time, the influences on orthotic practice. Methods: A qualitative approach was adopted utilising two focus groups (16 consenting participants in total; 15 podiatrists and 1 orthotist) in order to collect the data. An opening question “What factors influence your orthotic practice?” was followed with trigger questions, which were used to maintain focus. The dialogue was recorded digitally, transcribed verbatim and a thematic framework was used to analyse the data. Results: There were five themes: (i) influences on current practice, (ii) components of current practice, (iii) barriers to technology being used in clinical practice, (iv) how technology could enhance foot orthoses prescription and measurement of outcomes, and (v) how technology could provide information for practitioners and patients. A final global theme was agreed by the researchers and the participants: ‘Current orthotic practice is variable and does not embrace technology as it is perceived as being not fit for purpose in the clinical environment. However, practitioners do have a desire for technology that is usable and enhances patient focussed assessment, the interventions, the clinical outcomes and the patient’s engagement throughout these processes’. Conclusions: In relation to prescribing foot orthoses, practice varies considerably due to multiple influences. Measurement of outcomes from orthotic practice is a priority but there are no current norms for achieving this. There have been attempts by practitioners to integrate technology into their practice, but with largely negative experiences. The process of technology development needs to improve and have a more practice, rather than technology focus

Releasing incompatible males drives strong suppression across populations of wild and Wolbachia-carrying Aedes aegypti in Australia

Releasing sterile or incompatible male insects is a proven method of population management in agricultural systems with the potential to revolutionize mosquito control. Through a collaborative venture with the “Debug” Verily Life Sciences team, we assessed the incompatible insect technique (IIT) with the mosquito vector Aedes aegypti in northern Australia in a replicated treatment control field trial. Backcrossing a US strain of Ae. aegypti carrying Wolbachia wAlbB from Aedes albopictus with a local strain, we generated a wAlbB2-F4 strain incompatible with both the wild-type (no Wolbachia) and wMel-Wolbachia Ae. aegypti now extant in North Queensland. The wAlbB2-F4 strain was manually mass reared with males separated from females using Verily sex-sorting technologies to obtain no detectable female contamination in the field. With community consent, we delivered a total of three million IIT males into three isolated landscapes of over 200 houses each, releasing ∼50 males per house three times a week over 20 wk. Detecting initial overflooding ratios of between 5:1 and 10:1, strong population declines well beyond 80% were detected across all treatment landscapes when compared to controls. Monitoring through the following season to observe the ongoing effect saw one treatment landscape devoid of adult Ae. aegypti early in the season. A second landscape showed reduced adults, and the third recovered fully. These encouraging results in suppressing both wild-type and wMel-Ae. aegypti confirms the utility of bidirectional incompatibility in the field setting, show the IIT to be robust, and indicate that the removal of this arbovirus vector from human-occupied landscapes may be achievable

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm&lt; 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Establishment of wMel Wolbachia in Aedes aegypti mosquitoes and reduction of local dengue transmission in Cairns and surrounding locations in northern Queensland, Australia.

Background: The wMel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and subsequently shown in laboratory studies to reduce transmission of a range of viruses including dengue, Zika, chikungunya, yellow fever, and Mayaro viruses that cause human disease. Here we report the entomological and epidemiological outcomes of staged deployment of Wolbachia across nearly all significant dengue transmission risk areas in Australia. Methods: The  wMel strain of  Wolbachia was backcrossed into the local  Aedes aegypti genotype (Cairns and Townsville backgrounds) and mosquitoes were released in the field by staff or via community assisted methods. Mosquito monitoring was undertaken and mosquitoes were screened for the presence of  Wolbachia. Dengue case notifications were used to track dengue incidence in each location before and after releases. Results: Empirical analyses of the Wolbachia mosquito releases, including data on the density, frequency and duration of Wolbachia mosquito releases, indicate that Wolbachia can be readily established in local mosquito populations, using a variety of deployment options and over short release durations (mean release period 11 weeks, range 2-22 weeks). Importantly, Wolbachia frequencies have remained stable in mosquito populations since releases for up to 8 years. Analysis of dengue case notifications data demonstrates near-elimination of local dengue transmission for the past five years in locations where Wolbachia has been established. The regression model estimate of Wolbachia intervention effect from interrupted time series analyses of case notifications data prior to and after releases, indicated a 96% reduction in dengue incidence in Wolbachia treated populations (95% confidence interval: 84 - 99%). Conclusion: Deployment of the wMel strain of Wolbachia into local Ae. aegypti populations across the Australian regional cities of Cairns and most smaller regional communities with a past history of dengue has resulted in the reduction of local dengue transmission across all deployment areas