Eye-movements aid the control of locomotion

Eye-movements have long been considered a problem when trying to understand the visual control of locomotion. They transform the retinal image from a simple expanding pattern of moving texture elements (pure optic flow), into a complex combination of translation and rotation components (retinal flow). In this article we investigate whether there are measurable advantages to having an active free gaze, over a static gaze or tracking gaze, when steering along a winding path. We also examine patterns of free gaze behavior to determine preferred gaze strategies during active locomotion. Participants were asked to steer along a computer-simulated textured roadway with free gaze, fixed gaze, or gaze tracking the center of the roadway. Deviation of position from the center of the road was recorded along with their point of gaze. It was found that visually tracking the middle of the road produced smaller steering errors than for fixed gaze. Participants performed best at the steering task when allowed to sample naturally from the road ahead with free gaze. There was some variation in the gaze strategies used, but sampling was predominantly of areas proximal to the center of the road. These results diverge from traditional models of flow analysis.

Receding and disparity cues aid relaxation of accommodation

Purpose. Accommodation can mask hyperopia and reduce the accuracy of non-cycloplegic refraction. It is, therefore, important to minimize accommodation to obtain a measure of hyperopia as accurate as possible. To characterize the parameters required to measure the maximally hyperopic error using photorefraction, we used different target types and distances to determine which target was most likely to maximally relax accommodation and thus more accurately detect hyperopia in an individual. Methods. A PlusoptiX SO4 infra-red photorefractor was mounted in a remote haploscope which presented the targets. All participants were tested with targets at four fixation distances between 0.3 and 2 m containing all combinations of blur, disparity, and proximity/looming cues. Thirty-eight infants (6 to 44 weeks) were studied longitudinally, and 104 children [4 to 15 years (mean 6.4)] and 85 adults, with a range of refractive errors and binocular vision status, were tested once. Cycloplegic refraction data were available for a sub-set of 59 participants spread across the age range. Results. The maximally hyperopic refraction (MHR) found at any time in the session was most frequently found when fixating the most distant targets and those containing disparity and dynamic proximity/looming cues. Presence or absence of blur was less significant, and targets in which only single cues to depth were present were also less likely to produce MHR. MHR correlated closely with cycloplegic refraction (r = 0.93, mean difference 0.07 D, p = n.s., 95% confidence interval +/-<0.25 D) after correction by a calibration factor. Conclusions. Maximum relaxation of accommodation occurred for binocular targets receding into the distance. Proximal and disparity cues aid relaxation of accommodation to a greater extent than blur, and thus non-cycloplegic refraction targets should incorporate these cues. This is especially important in screening contexts with a brief opportunity to test for significant hyperopia. MHR in our laboratory was found to be a reliable estimation of cycloplegic refraction. (Optom Vis Sci 2009;86:1276-1286)

A novel experimental method for measuring vergence and accommodation responses to the main near visual cues in typical and atypical groups

Binocular disparity, blur, and proximal cues drive convergence and accommodation. Disparity is considered to be the main vergence cue and blur the main accommodation cue. We have developed a remote haploscopic photorefractor to measure simultaneous vergence and accommodation objectively in a wide range of participants of all ages while fixating targets at between 0.3 and 2 m. By separating the three main near cues, we can explore their relative weighting in three-, two-, one-, and zero-cue conditions. Disparity can be manipulated by remote occlusion; blur cues manipulated by using either a Gabor patch or a detailed picture target; looming cues by either scaling or not scaling target size with distance. In normal orthophoric, emmetropic, symptom-free, naive visually mature participants, disparity was by far the most significant cue to both vergence and accommodation. Accommodation responses dropped dramatically if disparity was not available. Blur only had a clinically significant effect when disparity was absent. Proximity had very little effect. There was considerable interparticipant variation. We predict that relative weighting of near cue use is likely to vary between clinical groups and present some individual cases as examples. We are using this naturalistic tool to research strabismus, vergence and accommodation development, and emmetropization.

Finite- N effects for ideal polymer chains near a flat impenetrable wall

This paper addresses the statistical mechanics of ideal polymer chains next to a hard wall. The principal quantity of interest, from which all monomer densities can be calculated, is the partition function, G N(z) , for a chain of N discrete monomers with one end fixed a distance z from the wall. It is well accepted that in the limit of infinite N , G N(z) satisfies the diffusion equation with the Dirichlet boundary condition, G N(0) = 0 , unless the wall possesses a sufficient attraction, in which case the Robin boundary condition, G N(0) = - x G N ′(0) , applies with a positive coefficient, x . Here we investigate the leading N -1/2 correction, D G N(z) . Prior to the adsorption threshold, D G N(z) is found to involve two distinct parts: a Gaussian correction (for z <~Unknown control sequence '\lesssim' aN 1/2 with a model-dependent amplitude, A , and a proximal-layer correction (for z <~Unknown control sequence '\lesssim' a described by a model-dependent function, B(z).

Non-genomic effects of PPARgamma ligands: inhibition of GPVI-stimulated platelet activation

BACKGROUND: Peroxisome proliferator-activated receptor-(gamma) (PPAR(gamma)) is expressed in human platelets although in the absence of genomic regulation in these cells, its functions are unclear. OBJECTIVE: In the present study, we aimed to demonstrate the ability of PPAR(gamma) ligands to modulate collagen-stimulated platelet function and suppress activation of the glycoprotein VI (GPVI) signaling pathway. METHODS: Washed platelets were stimulated with PPAR(gamma) ligands in the presence and absence of PPAR(gamma) antagonist GW9662 and collagen-induced aggregation was measured using optical aggregometry. Calcium levels were measured by spectrofluorimetry in Fura-2AM-loaded platelets and tyrosine phosphorylation levels of receptor-proximal components of the GPVI signaling pathway were measured using immunoblot analysis. The role of PPAR(gamma) agonists in thrombus formation was assessed using an in vitro model of thrombus formation under arterial flow conditions. RESULTS: PPAR(gamma) ligands inhibited collagen-stimulated platelet aggregation that was accompanied by a reduction in intracellular calcium mobilization and P-selectin exposure. PPAR(gamma) ligands inhibited thrombus formation under arterial flow conditions. The incorporation of GW9662 reversed the inhibitory actions of PPAR(gamma) agonists, implicating PPAR(gamma) in the effects observed. Furthermore, PPAR(gamma) ligands were found to inhibit tyrosine phosphorylation levels of multiple components of the GPVI signaling pathway. PPAR(gamma) was found to associate with Syk and LAT after platelet activation. This association was prevented by PPAR(gamma) agonists, indicating a potential mechanism for PPAR(gamma) function in collagen-stimulated platelet activation. CONCLUSIONS: PPAR(gamma) agonists inhibit the activation of collagen-stimulation of platelet function through modulation of early GPVI signalling.

Cellular and molecular investigations into the development of the pectoral girdle

The forelimbs of higher vertebrates are composed of two portions: the appendicular region (stylopod, zeugopod and autopod) and the less prominent proximal girdle elements (scapula and clavicle) that brace the limb to the main trunk axis. We show that the formation of the muscles of the proximal limb occurs through two distinct mechanisms. The more superficial girdle muscles (pectoral and latissimus dorsi) develop by the “In–Out” mechanism whereby migration of myogenic cells from the somites into the limb bud is followed by their extension from the proximal limb bud out onto the thorax. In contrast, the deeper girdle muscles (e.g. rhomboideus profundus and serratus anterior) are induced by the forelimb field which promotes myotomal extension directly from the somites. Tbx5 inactivation demonstrated its requirement for the development of all forelimb elements which include the skeletal elements, proximal and distal muscles as well as the sternum in mammals and the cleithrum of fish. Intriguingly, the formation of the diaphragm musculature is also dependent on the Tbx5 programme. These observations challenge our classical views of the boundary between limb and trunk tissues. We suggest that significant structures located in the body should be considered as components of the forelimb.

LXR as a novel antithrombotic target

Liver X receptors (LXRs) are transcription factors involved in the regulation of cholesterol homeostasis. LXR ligands have athero-protective properties independent of their effects on cholesterol metabolism. Platelets are involved in the initiation of atherosclerosis and despite being anucleate express nuclear receptors. We hypothesized that the athero-protective effects of LXR ligands could be in part mediated through platelets and therefore explored the potential role of LXR in platelets. Our results show that LXR-β is present in human platelets and the LXR ligands, GW3965 and T0901317, modulated nongenomically platelet aggregation stimulated by a range of agonists. GW3965 caused LXR to associate with signaling components proximal to the collagen receptor, GPVI, suggesting a potential mechanism of LXR action in platelets that leads to diminished platelet responses. Activation of platelets at sites of atherosclerotic lesions results in thrombosis preceding myocardial infarction and stroke. Using an in vivo model of thrombosis in mice, we show that GW3965 has antithrombotic effects, reducing the size and the stability of thrombi. The athero-protective effects of GW3965, together with its novel antiplatelet/thrombotic effects, indicate LXR as a potential target for prevention of athero-thrombotic disease.

Decreased accommodation during decompensation of distance exotropia

Objective. Disparity cues can be a major drive to accommodation via the CA/C (convergence accommodation to convergence) linkage but, on decompensation of exotropia, disparity cues are extinguished by suppression, so this drive is lost. This study investigated accommodation and vergence responses to disparity, blur and proximal cues in a group of distance exotropes aged between 4-11 years both during decompensation and when exotropic. Methods. 19 participants with distance exotropia were tested using a PlusoptiXSO4 photorefractor set in a remote haploscopic device which assessed simultaneous vergence and accommodation to a range of targets incorporating different combinations of blur, disparity and proximal cues at four fixation distances between 2m and 33cm. Responses on decompensation were compared to those from the same children when their deviation was controlled. Results. Manifest exotropia was more common in the more impoverished cue conditions. When decompensated for near, mean accommodation gain for the all-cue (naturalistic) target reduced significantly (p<0.0001), with resultant mean under-accommodation of 2.33D at 33cm. The profile of near cues usage changed after decompensation, with blur and proximity driving residual responses, but these remaining cues did not compensate for loss of accommodation caused by the removal of disparity. Conclusions. Accommodation often reduces on decompensation of distance exotropia as the drive from convergence is extinguished, providing a further reason to try to prevent decompensation for near.

Ultra-distal tephra deposits from super-eruptions: examples from Toba, Indonesia and Taupo Volcanic Zone, New Zealand

Voluminous rhyolitic eruptions from Toba, Indonesia, and Taupo Volcanic Zone (TVZ), New Zealand, have dispersed volcanic ash over vast areas in the late Quaternary. The ~74 ka Youngest Toba Tuff (YTT) eruption deposited ash over the Bay of Bengal and the Indian subcontinent to the west. The ~340 ka Whakamaru eruption (TVZ) deposited the widespread Rangitawa Tephra, dominantly to the southeast (in addition to occurrences northwest of vent), extending across the landmass of New Zealand, and the South Pacific Ocean and Tasman Sea, with distal terrestrial exposures on the Chatham Islands. These super-eruptions involved ~2500 km^3 and ~1500 km3 of magma (dense-rock equivalent; DRE), respectively. Ultra-distal terrestrial exposures of YTT at two localities in India, Middle Son Valley, Madhya Pradesh, and Jurreru River Valley, Andhra Pradesh, at distances of >2000 km from the source caldera, show a basal ‘primary’ ashfall unit ~4 cm thick, although deposits containing reworked ash are up to ~3 m in total thickness. Exposures of Rangitawa Tephra on the Chatham Islands, >900 km from the source caldera, are ~15-30 cm thick. At more proximal localities (~200 km from source), Rangitawa Tephra is ~55-70 cm thick and characterized by a crystal-rich basal layer and normal grading. Both distal tephra deposits are characterized by very-fine ash (with high PM10 fractions) and are crystal-poor. Glass chemistry, stratigraphy and grain-size data for these distal tephra deposits are presented with comparisons of their correlation, dispersal and preservation. Using field observations, ash transport and deposition were modeled for both eruptions using a semi-analytical model (HAZMAP), with assumptions concerning average wind direction and strength during eruption, column shape and vent size. Model outputs provide new insights into eruption dynamics and better estimates of eruption volumes associ- ated with tephra fallout. Modeling based on observed YTT distal tephra thicknesses indicate a relatively low (<40 km high), very turbulent eruption column, consistent with deposition from a co-ignimbrite cloud extending over a broad region. Similarly, the Whakamaru eruption was modeled as producing a predominantly Plinian column (~45 km high), with dispersal to the southeast by strong prevailing winds. Significant ash fallout of the main dispersal direction, to the northwest of source, cannot be replicated in this modeling. The widespread dispersal of large volumes of fine ash from both eruptions may have had global environmental consequences, acutely affecting areas up to thousands of kilometers from vent.

A randomised crossover study investigating the effects of galacto-oligosaccharides on the faecal microbiota in men and women over 50 years of age

Faecal microbial changes associated with ageing include reduced bifidobacteria numbers. These changes coincide with an increased risk of disease development. Prebiotics have been observed to increase bifidobacteria numbers within humans. The present study aimed to determine if prebiotic galacto-oligosaccharides (GOS) could benefit a population of men and women of 50 years and above, through modulation of faecal microbiota, fermentation characteristics and faecal water genotoxicity. A total of thirty-seven volunteers completed this randomised, double-blind, placebo-controlled crossover trial. The treatments – juice containing 4 g GOS and placebo – were consumed twice daily for 3 weeks, preceded by 3-week washout periods. To study the effect of GOS on different large bowel regions, three-stage continuous culture systems were conducted in parallel using faecal inocula from three volunteers. Faecal samples were microbially enumerated by quantitative PCR. In vivo, following GOS intervention, bifidobacteria were significantly more compared to post-placebo (P = 0·02). Accordingly, GOS supplementation had a bifidogenic effect in all in vitro system vessels. Furthermore, in vessel 1 (similar to the proximal colon), GOS fermentation led to more lactobacilli and increased butyrate. No changes in faecal water genotoxicity were observed. To conclude, GOS supplementation significantly increased bifidobacteria numbers in vivo and in vitro. Increased butyrate production and elevated bifidobacteria numbers may constitute beneficial modulation of the gut microbiota in a maturing population.

Expression-system-dependent modulation of HIV-1 envelope glycoprotein antigenicity and immunogenicity.

Recombinant expression systems differ in the type of glycosylation they impart on expressed antigens such as the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins, potentially affecting their biological properties. We performed head-to-head antigenic, immunogenic and molecular profiling of two distantly related Env surface (gp120) antigens produced in different systems: (a) mammalian (293 FreeStyle cells; 293F) cells in the presence of kifunensine, which impart only high-mannose glycans; (b) insect cells (Spodoptera frugiperda, Sf9), which confer mainly paucimannosidic glycans; (c) Sf9 cells recombinant for mammalian glycosylation enzymes (Sf9 Mimic), which impart high-mannose, hybrid and complex glycans without sialic acid; and (d) 293F cells, which impart high-mannose, hybrid and complex glycans with sialic acid. Molecular models revealed a significant difference in gp120 glycan coverage between the Sf9-derived and wild-type mammalian-cell-derived material that is predicted to affect ligand binding sites proximal to glycans. Modeling of solvent-exposed surface electrostatic potentials showed that sialic acid imparts a significant negative surface charge that may influence gp120 antigenicity and immunogenicity. Gp120 expressed in systems that do not incorporate sialic acid displayed increased ligand binding to the CD4 binding and CD4-induced sites compared to those expressed in the system that do, and imparted other more subtle differences in antigenicity in a gp120 subtype-specific manner. Non-sialic-acid-containing gp120 was significantly more immunogenic than the sialylated version when administered in two different adjuvants, and induced higher titers of antibodies competing for CD4 binding site ligand-gp120 interaction. These findings suggest that non-sialic-acid-imparting systems yield gp120 immunogens with modified antigenic and immunogenic properties, considerations that should be considered when selecting expression systems for glycosylated antigens to be used for structure-function studies and for vaccine use.

Holocene settlement shifts and paleoenvironments on the Central Iranian Plateau: investigating linked systems

For thousands of years, humans have inhabited locations that are highly vulnerable to the impacts of climate change, earthquakes, and floods. In order to investigate the extent to which Holocene environmental changes may have impacted on cultural evolution, we present new geologic, geomorphic, and chronologic data from the Qazvin Plain in northwest Iran that provides a backdrop of natural environmental changes for the simultaneous cultural dynamics observed on the Central Iranian Plateau. Well-resolved archaeological data from the neighbouring settlements of Zagheh (7170—6300 yr BP), Ghabristan (6215—4950 yr BP) and Sagzabad (4050—2350 yr BP) indicate that Holocene occupation of the Hajiarab alluvial fan was interrupted by a 900 year settlement hiatus. Multiproxy climate data from nearby lakes in northwest Iran suggest a transition from arid early-Holocene conditions to more humid middle-Holocene conditions from c. 7550 to 6750 yr BP, coinciding with the settlement of Zagheh, and a peak in aridity at c. 4550 yr BP during the settlement hiatus. Palaeoseismic investigations indicate that large active fault systems in close proximity to the tell sites incurred a series of large (MW ~7.1) earthquakes with return periods of ~500—1000 years during human occupation of the tells. Mapping and optically stimulated luminescence (OSL) chronology of the alluvial sequences reveals changes in depositional style from coarse-grained unconfined sheet flow deposits to proximal channel flow and distally prograding alluvial deposits sometime after c. 8830 yr BP, possibly reflecting an increase in moisture following the early-Holocene arid phase. The coincidence of major climate changes, earthquake activity, and varying sedimentation styles with changing patterns of human occupation on the Hajiarab fan indicate links between environmental and anthropogenic systems. However, temporal coincidence does not necessitate a fundamental causative dependency.

Sustained polymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes and ribozymes: in vitro and in vivo studies

Small interfering RNA (siRNA), antisense oligonucleotides (ODNs), ribozymes and DNAzymes have emerged as sequence-specific inhibitors of gene expression that may have therapeutic potential in the treatment of a wide range of diseases. Due to their rapid degradation in vivo, the efficacy of naked gene silencing nucleic acids is relatively short lived. The entrapment of these nucleic acids within biodegradable sustained-release delivery systems may improve their stability and reduce the doses required for efficacy. In this study, we have evaluated the potential in vitro and in vivo use of biodegradable poly (d,l-lactide-co-glycolide) copolymer (PLGA) microspheres as sustained delivery devices for ODNs, ribozyme, siRNA and DNA enzymes. In addition, we investigated the release of ODN conjugates bearing 5′-end lipophilic groups. The in vitro sustained release profiles of microsphere-entrapped nucleic acids were dependent on variables such as the type of nucleic acid used, the nature of the lipophilic group, and whether the nucleic acid used was single or double stranded. For in vivo studies, whole body autoradiography was used to monitor the bio-distribution of either free tritium-labelled ODN or that entrapped within PLGA microspheres following subcutaneous administration in Balb-c mice. The majority of the radioactivity associated with free ODN was eliminated within 24 h whereas polymer-released ODN persisted in organs and at the site of administration even after seven days post-administration. Polymer microsphere released ODN exhibited a similar tissue and cellular tropism to the free ODN. Micro-autoradiography analyses of the liver and kidneys showed similar bio-distribution for polymer-released and free ODNs with the majority of radioactivity being concentrated in the proximal convoluted tubules of the kidney and in the Kupffer cells of the liver. These findings suggest that biodegradable PLGA microspheres offer a method for improving the in vivo sustained delivery of gene silencing nucleic acids, and hence are worthy of further investigation as delivery systems for these macromolecules.

Intermittent Escherichia coli O157:H7 colonisation at the terminal rectum mucosa of conventionally-reared lambs

In cattle, the lymphoid rich regions of the rectal-anal mucosa at the terminal rectum are the preferred site for Escherichia coli O157:H7 colonisation. All cattle infected by rectal swab administration demonstrate long-term E. coli O157:H7 colonisation, whereas orally challenged cattle do not demonstrate long-term E. coli O157:H7 colonisation in all animals. Oral, but not rectal challenge of sheep with E. coli O157:H7 has been reported, but an exact site for colonisation in sheep is unknown. To determine if E. coli O157:H7 can effectively colonise the ovine terminal rectum, in vitro organ culture (IVOC) was initiated. Albeit sparsely, large, densely packed E. coli O157:H7 micro-colonies were observed on the mucosa of ovine and control bovine terminal rectum explants. After necropsy of orally inoculated lambs, bacterial enumeration of the proximal and distal gastrointestinal tract did suggest a preference for E. coli O157:H7 colonisation at the ovine terminal rectum, albeit for both lymphoid rich and non-lymphoid sites. As reported for cattle, rectal inoculation studies were then conducted to determine if all lambs would demonstrate persistent colonisation at the terminal rectum. After necropsy of E. coli O157:H7 rectally inoculated lambs, most animals were not colonised at gastrointestinal sites proximal to the rectum, however, large densely packed micro-colonies of E. coli O157:H7 were observed on the ovine terminal rectum mucosa. Nevertheless, at the end point of the study (day 14), only one lamb had E. coli O157:H7 micro-colonies associated with the terminal rectum mucosa. A comparison of E. coli O157:H7 shedding yielded a similar pattern of persistence between rectally and orally inoculated lambs. The inability of E. coli O157:H7 to effectively colonise the terminal rectum mucosa of all rectally inoculated sheep in the long term, suggests that E. coli O157:H7 may colonise this site, but less effectively than reported previously for cattle.

The gut microbiota elicits a profound metabolic reorientation in the mouse jejunal mucosa during conventionalisation

Objective: Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region.Design: Germ-free mice aged 8-10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, (1)H NMR metabonomics and microbiota phylogenetic profiling analyses were used.Results: The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4-30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus.Conclusion: This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance.