The Effects of Drugs on Conduction and Transmission in Autonomically-Innervated Smooth Muscle

1. The prejunctional actions of a number of Ca 2+ channel antagonists were investigated. Their effects were assessed on both nerve action potential (AP) conduction and neuromuscular transmission in the vas deferens and internal anal sphincter (i.a.s.) of the guinea-pig and in the rat anococcygeus. Nerve APs were recorded extracellularly with a suction electrode and transmitter release measured by intracellular electrical recording of smooth muscle junction potentials and analysis of the overflow of radiolabelled transmitter

Perceptual impairment in face identification with poor sleep

Previous studies have shown impaired memory for faces following restricted sleep. However, it is not known whether lack of sleep impairs performance on face identification tasks that do not rely on recognition memory, despite these tasks being more prevalent in security and forensic professions—for example, in photo-ID checks at national borders. Here we tested whether poor sleep affects accuracy on a standard test of face-matching ability that does not place demands on memory: the Glasgow Face-Matching Task (GFMT). In Experiment 1, participants who reported sleep disturbance consistent with insomnia disorder show impaired accuracy on the GFMT when compared with participants reporting normal sleep behaviour. In Experiment 2, we then used a sleep diary method to compare GFMT accuracy in a control group to participants reporting poor sleep on three consecutive nights—and again found lower accuracy scores in the short sleep group. In both experiments, reduced face-matching accuracy in those with poorer sleep was not associated with lower confidence in their decisions, carrying implications for occupational settings where identification errors made with high confidence can have serious outcomes. These results suggest that sleep-related impairments in face memory reflect difficulties in perceptual encoding of identity, and point towards metacognitive impairment in face matching following poor sleep

Genomic analysis of Pyrenophora teres : avirulence gene mapping, karyotyping and genetic map construction

Pyrenophora teres Drechs. (anamorph: Drechslera teres (Sacc.) Shoem.) is the causal agent of barley net blotch. Net blotch is an economically important disease commonly found throughout the barley producing regions of the world. Significant financial losses result from yield reductions, ranging from 15-35%, and decreased grain quality. Despite its prevalence, it is unclear if the P. teres-barley pathosystem follows a gene-for-gene model, and more generally, little is known about its genetic organization. Three studies were initiated to address these questions.The first study investigated the genetic control of avirulence in P. teres. To establish an appropriate study system, a collection of ten net form (P. teres f. teres) and spot form (P. teres f. maculata) isolates were evaluated on a set of eight differential barley lines to identify two isolates with differential virulence on a specific host line. WRS 1906, exhibiting low virulence on the cultivar ‘Heartland,’ and WRS 1607, exhibiting high virulence, were mated and 67 progeny were isolated and phenotyped for virulence on Heartland. The population segregated in a 1:1 ratio, 34 avirulent to 33 virulent (Chi-square = 0.0, P = 1.0), indicating single gene control of WRS 1906 avirulence on Heartland. Bulked segregant analysis was used to identify six amplified fragment length polymorphism (AFLP) markers closely linked to the avirulence gene (AvrHeartland). This work provides evidence that the P. teres-barley pathosystem conforms to the gene-for-gene model.In the second study, five isolates of P. teres, representing both net and spot forms, were analyzed by the germ tube burst method (GTBM) and pulsed field gel electrophoresis (PFGE) to determine the species’ karyotype. Nine chromosomes were observed in all isolates using the GTBM and estimation of chromosome lengths varied from 0.5 to 3.0 µm. PFGE separated 7 to 8 bands depending on isolate, but analysis of bands by densitometry indicated nine chromosomes. Chromosome size ranged from 1.8 to ~6.0 Mb providing a genome size estimate of 32 to 39 Mb. Significant chromosome-length polymorphisms (CLP) were observed between isolates. These CLP did not hinder mating between mating-type compatible net form isolates. No particular CLP or individual chromosome could be associated with differences in disease symptoms observed between pathogen forms. This study provides the first karyotype of both P. teres forms and will assist genetic mapping of this pathogen.A genetic linkage map of P. teres f. teres, was constructed in the third study using the population of 67 progeny derived from the WRS 1906  WRS 1607 cross. The map consists of 138 markers including 114 AFLPs, 21 telomere RFLPs, the mating-type (MAT) locus and an avirulence locus (AvrHeartland) controlling interaction with barley cultivar ‘Heartland.’ Markers were distributed across 24 linkage groups ranging in length from 2 to 110 cM with an average marker interval of 8.5 cM. The total map length was 797 cM. A telomere-specific probe, consisting of the sequence (TTAGGC)4, was used to map 15 of the 18 telomeres. One of these telomeres mapped to within 3 cM of the AvrHeartland locus. Attempts to consolidate linkage groups by hybridizing markers to the electrophoretically separated chromosomes was unsuccessful because probes bound to multiple chromosomes, likely due to repetitive DNA within the probe. This is the first genetic map reported for this species and it will be a useful genetic tool for map-based cloning of the AvrHeartland gene tagged in this study. This research has provided a number of new insights into the net blotch pathogen and provides a useful research tool in the form of a genetic map. This information lays the foundation for further genetic study of P. teres and will complement studies on barley resistance to net blotch that may potentially lead to more durable resistance

A comparison of artificial driving sounds for automated vehicles

As automated vehicles currently do not provide sufficient feedback relating to the primary driving task, drivers have no assurance that an automated vehicle has understood and can cope with upcoming traffic situations [16]. To address this we conducted two user evaluations to investigate auditory displays in automated vehicles using different types of sound cues related to the primary driving sounds: acceleration, deceleration/braking, gear changing and indicating. Our first study compared earcons, speech and auditory icons with existing vehicle sounds. Our findings suggested that earcons were an effective alternative to existing vehicle sounds for presenting information related to the primary driving task. Based on these findings a second study was conducted to further investigate earcons modulated by different sonic parameters to present primary driving sounds. We discovered that earcons containing naturally mapped sonic parameters such as pitch and timbre were as effective as existing sounds in a simulated automated vehicle

Exploring how drivers perceive spatial earcons in automated vehicles

Automated vehicles seek to relieve the human driver from primary driving tasks, but this substantially diminishes the connection between driver and vehicle compared to manual operation. At present, automated vehicles lack any form of continual, appropriate feedback to re-establish this connection and offer a feeling of control. We suggest that auditory feedback can be used to support the driver in this context. A preliminary field study that explored how drivers respond to existing auditory feedback in manual vehicles was first undertaken. We then designed a set of abstract, synthesised sounds presented spatially around the driver, known as Spatial Earcons, that represented different primary driving sounds e.g. acceleration. To evaluate their effectiveness, we undertook a driving simulator study in an outdoor setting using a real vehicle. Spatial Earcons performed as well as Existing Vehicle Sounds during automated and manual driving scenarios. Subjective responses suggested Spatial Earcons produced an engaging driving experience. This paper argues that entirely new synthesised primary driving sounds, such as Spatial Earcons, can be designed for automated vehicles to replace Existing Vehicle Sounds. This creates new possibilities for presenting primary driving information in automated vehicles using auditory feedback, in order to re-establish a connection between driver and vehicle

Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics

Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (225Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods: Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [177Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results: Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [177Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions: This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225Ac labeled hu11B6, however emerging at a later timepoint

Unpacking Support Types in Online Health Communities: An Application of Attraction-Selection-Attrition Theory

Online communities are increasingly becoming part of the healthcare ecosystem, as they allow patients, family members and carers to connect and support each other at any time and from any location. This support can take many forms, including information, advice, esteem support and solidarity. Prior research has identified the Attraction-Selection-Attrition Theory as a promising framework for modelling and explaining how participants join, participate, and leave organizations in general (and online communities specifically), and how the actions of individuals effect the organization as a whole. However, it has not previously been applied specifically to online health communities (i.e. those that focus on physical and/or mental health). We propose to gather empirical evidence from a large online community that provides support for Australians effected by cancer. In doing so, we hope to develop evidence-based policies and procedures for growing, maintaining and moderating these communities