The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure.

The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive (SM22α)CaSR(Δflox/Δflox) [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.

Local adaptation at range edges: comparing elevation and latitudinal gradients.

Local adaptation at range edges influences species' distributions and how they respond to environmental change. However, the factors that affect adaptation, including gene flow and local selection pressures, are likely to vary across different types of range edge. We performed a reciprocal transplant experiment to investigate local adaptation in populations of Plantago lanceolata and P. major from central locations in their European range and from their latitudinal and elevation range edges (in northern Scandinavia and Swiss Alps, respectively). We also characterized patterns of genetic diversity and differentiation in populations using molecular markers. Range-centre plants of P. major were adapted to conditions at the range centre, but performed similarly to range-edge plants when grown at the range edges. There was no evidence for local adaptation when comparing central and edge populations of P. lanceolata. However, plants of both species from high elevation were locally adapted when compared with plants from high latitude, although the reverse was not true. This asymmetry was associated with greater genetic diversity and less genetic differentiation over the elevation gradient than over the latitudinal gradient. Our results suggest that adaptation in some range-edge populations could increase their performance following climate change. However, responses are likely to differ along elevation and latitudinal gradients, with adaptation more likely at high-elevation. Furthermore, based upon these results, we suggest that gene flow is unlikely to constrain adaptation in range-edge populations of these species.

Widespread phenotypic and genetic divergence along altitudinal gradients in animals.

Altitudinal gradients offer valuable study systems to investigate how adaptive genetic diversity is distributed within and between natural populations and which factors promote or prevent adaptive differentiation. The environmental clines along altitudinal gradients tend to be steep relative to the dispersal distance of many organisms, providing an opportunity to study the joint effects of divergent natural selection and gene flow. Temperature is one variable showing consistent altitudinal changes, and altitudinal gradients can therefore provide spatial surrogates for some of the changes anticipated under climate change. Here, we investigate the extent and patterns of adaptive divergence in animal populations along altitudinal gradients by surveying the literature for (i) studies on phenotypic variation assessed under common garden or reciprocal transplant designs and (ii) studies looking for signatures of divergent selection at the molecular level. Phenotypic data show that significant between-population differences are common and taxonomically widespread, involving traits such as mass, wing size, tolerance to thermal extremes and melanization. Several lines of evidence suggest that some of the observed differences are adaptively relevant, but rigorous tests of local adaptation or the link between specific phenotypes and fitness are sorely lacking. Evidence for a role of altitudinal adaptation also exists for a number of candidate genes, most prominently haemoglobin, and for anonymous molecular markers. Novel genomic approaches may provide valuable tools for studying adaptive diversity, also in species that are not amenable to experimentation.

Utility of optical see-through head mounted displays in augmented reality-assisted surgery: A systematic review.

This article presents a systematic review of optical see-through head mounted display (OST-HMD) usage in augmented reality (AR) surgery applications from 2013 to 2020. Articles were categorised by: OST-HMD device, surgical speciality, surgical application context, visualisation content, experimental design and evaluation, accuracy and human factors of human-computer interaction. 91 articles fulfilled all inclusion criteria. Some clear trends emerge. The Microsoft HoloLens increasingly dominates the field, with orthopaedic surgery being the most popular application (28.6%). By far the most common surgical context is surgical guidance (n=58) and segmented preoperative models dominate visualisation (n=40). Experiments mainly involve phantoms (n=43) or system setup (n=21), with patient case studies ranking third (n=19), reflecting the comparative infancy of the field. Experiments cover issues from registration to perception with very different accuracy results. Human factors emerge as significant to OST-HMD utility. Some factors are addressed by the systems proposed, such as attention shift away from the surgical site and mental mapping of 2D images to 3D patient anatomy. Other persistent human factors remain or are caused by OST-HMD solutions, including ease of use, comfort and spatial perception issues. The significant upward trend in published articles is clear, but such devices are not yet established in the operating room and clinical studies showing benefit are lacking. A focused effort addressing technical registration and perceptual factors in the lab coupled with design that incorporates human factors considerations to solve clear clinical problems should ensure that the significant current research efforts will succeed.

SERV-CT: A disparity dataset from cone-beam CT for validation of endoscopic 3D reconstruction.

In computer vision, reference datasets from simulation and real outdoor scenes have been highly successful in promoting algorithmic development in stereo reconstruction. Endoscopic stereo reconstruction for surgical scenes gives rise to specific problems, including the lack of clear corner features, highly specular surface properties and the presence of blood and smoke. These issues present difficulties for both stereo reconstruction itself and also for standardised dataset production. Previous datasets have been produced using computed tomography (CT) or structured light reconstruction on phantom or ex vivo models. We present a stereo-endoscopic reconstruction validation dataset based on cone-beam CT (SERV-CT). Two ex vivo small porcine full torso cadavers were placed within the view of the endoscope with both the endoscope and target anatomy visible in the CT scan. Subsequent orientation of the endoscope was manually aligned to match the stereoscopic view and benchmark disparities, depths and occlusions are calculated. The requirement of a CT scan limited the number of stereo pairs to 8 from each ex vivo sample. For the second sample an RGB surface was acquired to aid alignment of smooth, featureless surfaces. Repeated manual alignments showed an RMS disparity accuracy of around 2 pixels and a depth accuracy of about 2 mm. A simplified reference dataset is provided consisting of endoscope image pairs with corresponding calibration, disparities, depths and occlusions covering the majority of the endoscopic image and a range of tissue types, including smooth specular surfaces, as well as significant variation of depth. We assessed the performance of various stereo algorithms from online available repositories. There is a significant variation between algorithms, highlighting some of the challenges of surgical endoscopic images. The SERV-CT dataset provides an easy to use stereoscopic validation for surgical applications with smooth reference disparities and depths covering the majority of the endoscopic image. This complements existing resources well and we hope will aid the development of surgical endoscopic anatomical reconstruction algorithms.

Implicit domain adaptation with conditional generative adversarial networks for depth prediction in endoscopy.

PURPOSE: Colorectal cancer is the third most common cancer worldwide, and early therapeutic treatment of precancerous tissue during colonoscopy is crucial for better prognosis and can be curative. Navigation within the colon and comprehensive inspection of the endoluminal tissue are key to successful colonoscopy but can vary with the skill and experience of the endoscopist. Computer-assisted interventions in colonoscopy can provide better support tools for mapping the colon to ensure complete examination and for automatically detecting abnormal tissue regions. METHODS: We train the conditional generative adversarial network pix2pix, to transform monocular endoscopic images to depth, which can be a building block in a navigational pipeline or be used to measure the size of polyps during colonoscopy. To overcome the lack of labelled training data in endoscopy, we propose to use simulation environments and to additionally train the generator and discriminator of the model on unlabelled real video frames in order to adapt to real colonoscopy environments. RESULTS: We report promising results on synthetic, phantom and real datasets and show that generative models outperform discriminative models when predicting depth from colonoscopy images, in terms of both accuracy and robustness towards changes in domains. CONCLUSIONS: Training the discriminator and generator of the model on real images, we show that our model performs implicit domain adaptation, which is a key step towards bridging the gap between synthetic and real data. Importantly, we demonstrate the feasibility of training a single model to predict depth from both synthetic and real images without the need for explicit, unsupervised transformer networks mapping between the domains of synthetic and real data.

Prediction uncertainty of environmental change effects on temperate European biodiversity.

Observed patterns of species richness at landscape scale (gamma diversity) cannot always be attributed to a specific set of explanatory variables, but rather different alternative explanatory statistical models of similar quality may exist. Therefore predictions of the effects of environmental change (such as in climate or land cover) on biodiversity may differ considerably, depending on the chosen set of explanatory variables. Here we use multimodel prediction to evaluate effects of climate, land-use intensity and landscape structure on species richness in each of seven groups of organisms (plants, birds, spiders, wild bees, ground beetles, true bugs and hoverflies) in temperate Europe. We contrast this approach with traditional best-model predictions, which we show, using cross-validation, to have inferior prediction accuracy. Multimodel inference changed the importance of some environmental variables in comparison with the best model, and accordingly gave deviating predictions for environmental change effects. Overall, prediction uncertainty for the multimodel approach was only slightly higher than that of the best model, and absolute changes in predicted species richness were also comparable. Richness predictions varied generally more for the impact of climate change than for land-use change at the coarse scale of our study. Overall, our study indicates that the uncertainty introduced to environmental change predictions through uncertainty in model selection both qualitatively and quantitatively affects species richness projections.

Plant enemy-derived elicitors increase the foliar tannin concentration of Onobrychis viciifolia without a trade-off to growth.

BACKGROUND AND AIMS: Molecular experiments suggest that the regulation of the biosynthesis of condensed tannin (CT) is sensitive to the presence of plant enemies. The enemy-specific response of CT concentrations to simulated attacks by pathogenic fungi, bacteria or herbivores was studied in Onobrychis viciifolia grown at four levels of nutrient availability. It was hypothesized that CT concentrations increase in response to an attack, and that constitutive and induced levels of CT are higher at low than at high nutrient availability. Investment in CT was also predicted to be negatively related to plant growth. METHODS: Recently discovered substances by which plants recognize their opponents (i.e. elicitors) were used to simulate attacks to Onobrychis viciifolia grown at 0.0027, 0.075, 0.67 or 2 mm phosphorus in the nutrient solution. KEY RESULTS: Relative growth rate and final biomass (P < 0.001) were highest at 0.67 mm of phosphorus. CT concentrations decreased with increasing phosphorus availability, from 94.9 to 69.0 mg g(-1) leaf dry weight (P < 0.001). Compared with unscathed plants, sterile mere mechanical wounding reduced tannin concentrations from 83.8 to 69.3 mg g(-1) leaf dry weight (P < 0.01). Local CT concentrations were higher when wounded leaves were additionally treated with fungal (+15.9 %), bacterial (+19.6 %) or insect (+31.0 %) elicitors (each elicitor; P < 0.05); however, only the insect elicitor (saliva of the lepidopteron Spodoptera littoralis) induced CT concentrations higher than those of unscathed leaves. CONCLUSIONS: CT concentrations were inducible in the vicinity of the wound but the level of induction was unrelated to the nutrient status of the plant. There was no evidence of a growth-defence trade-off. The inverse relationship between CT concentrations and nutrient availability appears to reflect passive growth dilution at high nutrient availability, rather than surplus CT production at low nutrient availability.

Food-poisoning and commercial air travel.

With the introduction of budget airlines and greater competitiveness amongst all airlines, air travel has now become an extremely popular form of travel, presenting its own unique set of risks from food poisoning. Foodborne illness associated with air travel is quite uncommon in the modern era. However, when it occurs, it may have serious implications for passengers and when crew are affected, has the potential to threaten safety. Quality, safe, in-flight catering relies on high standards of food preparation and storage; this applies at the airport kitchens (or at subcontractors' facilities), on the aircraft and in the transportation vehicles which carry the food from the ground source to the aircraft. This is especially challenging in certain countries. Several foodborne outbreaks have been recorded by the airline industry as a result of a number of different failures of these systems. These have provided an opportunity to learn from past mistakes and current practice has, therefore, reached such a standard so as to minimise risk of failures of this kind. This review examines: (i) the origin of food safety in modern commercial aviation; (ii) outbreaks which have occurred previously relating to aviation travel; (iii) the microbiological quality of food and water on board commercial aircraft; and (iv) how Hazard Analysis Critical Control Points may be employed to maintain food safety in aviation travel.

Cadaver validation of intensity-based ultrasound to CT registration.

A method is presented for the rigid registration of tracked B-mode ultrasound images to a CT volume of a femur and pelvis. This registration can allow tracked surgical instruments to be aligned with the CT image or an associated preoperative plan. Our method is fully automatic and requires no manual segmentation of either the ultrasound images or the CT volume. The parameter which is directly related to the speed of sound through tissue has also been included in the registration optimisation process. Experiments have been carried out on six cadaveric femurs and three cadaveric pelves. Registration results were compared with a "gold standard" registration acquired using bone implanted fiducial markers. Results show the registration method to be accurate, on average, to 1.6 mm root-mean-square target registration error.

Iron binding to caseins in the presence of orthophosphate.

As adding >5mM ferric chloride to sodium caseinate solutions results in protein precipitation, the effects of orthophosphate (0-64 mM) addition to sodium caseinate solution (2% w/v protein) on iron-induced aggregation of the caseins were studied at pH 6.8. Up to 20mM ferric chloride could be added to sodium caseinate solution containing 32 mM orthophosphate without any protein precipitation. The addition of iron to sodium caseinate solution containing orthophosphate reduced the diffusible phosphorus content in a concentration-dependent manner. Added iron appeared to interact simultaneously with phosphoserine on the caseins and inorganic phosphorus. The relative sizes of the casein aggregates were governed by the concentration of orthophosphate and the aggregates consisted of all casein fractions, even at the lowest level of ferric chloride addition (5mM). It is hypothesised that the addition of iron to caseins in the presence of orthophosphate results in the formation of colloidal structures involving casein-iron-orthophosphate interactions.

Tissue deformation and shape models in image-guided interventions: a discussion paper.

This paper promotes the concept of active models in image-guided interventions. We outline the limitations of the rigid body assumption in image-guided interventions and describe how intraoperative imaging provides a rich source of information on spatial location of anatomical structures and therapy devices, allowing a preoperative plan to be updated during an intervention. Soft tissue deformation and variation from an atlas to a particular individual can both be determined using non-rigid registration. Established methods using free-form deformations have a very large number of degrees of freedom. Three examples of deformable models--motion models, biomechanical models and statistical shape models--are used to illustrate how prior information can be used to restrict the number of degrees of freedom of the registration algorithm and thus provide active models for image-guided interventions. We provide preliminary results from applications for each type of model.

Image-guided navigation in oral and maxillofacial surgery.

Image-guided surgery is the logical extension of imaging as it integrates previously acquired radiological or nuclear medicine images with the operative field. In conventional image-guided surgery, a surgeon uses a surgical instrument or a pointer to establish correspondence between features in the preoperative images and the surgical scene. This is not ideal because the surgeon has to look away from the operative field to view the data. Augmented reality guidance systems offer a solution to this problem but are limited by deformation of soft tissues. Real-time intraoperative imaging offers a potential solution but is currently only experimental. The additional precision and confidence that this technology provides make it a useful tool, and recent advances in image-guided surgery offer new opportunities in the field of oral and maxillofacial surgery. Here, we review the development, current technologies, and applications of image-guided surgery and illustrate them with two case reports.

Applications of combinatorial chemistry to drug design and development.

This article is a subjective review of the literature from 1998 to April 1999 describing combinatorial chemistry as applied to drug discovery. The first two sections cover proteinase inhibition and small molecule lead discovery for other target classes. The final section describes those combinatorial chemistry-related technologies we think most likely to impact on drug discovery in the future.

Changes in germinability, ABA content and ABA embryonic sensitivity in developing seeds of Sorghum bicolor (L.) Moench. induced by water stress during grain filling.

The effect of intermittent water stress during grain filling on the germinability of developing seeds of S. bicolor was investigated. The drought treatment was imposed in cycles within the maturation period by withholding water for 5-6 days, rewatering at the end of each drought cycle and withholding water again. Changes in abscisic acid (ABA) content and embryonic sensitivity to ABA in the maturing seeds were also monitored in order to find out if there were any parallel changes with seed germinability resulting from drought conditions. Seeds developing in plants subjected to drought showed a high level of germinability earlier in the maturation period than did control seeds; consequently, they were less resistant to pre-harvest sprouting as shown when panicles were exposed to high humidity conditions. Very high levels of ABA accumulated in the early stages of development in seeds maturing on water-stressed mother plants; however. ABA content fell markedly when the seeds stopped growing, and remained significantly below those recorded in control seeds until the end of the maturation period. Development under drought conditions decreased the sensitivity of the isolated embryo to exogenous ABA by about 10-fold. The good agreement found between germinability, endogenous ABA concentrations and embryo sensitivity to ABA at different stages of development, suggests a key role for ABA as a major inhibitor of precocious germination and shows that changes in germinability caused by water stress during grain filling are likely to be related to changes in ABA pool size in the developing seed.

Design and evaluation of a system for microscope-assisted guided interventions (MAGI).

The problem of providing surgical navigation using image overlays on the operative scene can be split into four main tasks--calibration of the optical system; registration of preoperative images to the patient; system and patient tracking, and display using a suitable visualization scheme. To achieve a convincing result in the magnified microscope view a very high alignment accuracy is required. We have simulated an entire image overlay system to establish the most significant sources of error and improved each of the stages involved. The microscope calibration process has been automated. We have introduced bone-implanted markers for registration and incorporated a locking acrylic dental stent (LADS) for patient tracking. The LADS can also provide a less-invasive registration device with mean target error of 0.7 mm in volunteer experiments. These improvements have significantly increased the alignment accuracy of our overlays. Phantom accuracy is 0.3-0.5 mm and clinical overlay errors were 0.5-1.0 mm on the bone fiducials and 0.5-4 mm on target structures. We have improved the graphical representation of the stereo overlays. The resulting system provides three-dimensional surgical navigation for microscope-assisted guided interventions (MAGI).

Palatability of British trees to insects: constitutive and induced defences.

Undamaged foliage of sixteen species of broadleaved trees was assessed for background (constitutive) palatability using larvae of Spodoptera littoralis (Lepidoptera) in laboratory bioassays. Palatability (dry weight consumed in 48 h) varied significantly between species and exhibited a four-fold range. Leaves of fifteen species were damaged artificially in the field and offered with control (undamaged) leaves to Spodoptera after 48 h and two weeks on the tree. Leaves adjacent to the damaged ones were similarly tested. Ten species exhibited significant (P<0.02) wound induced declines in palatability; damaged and adjacent foliage was involved. Although there was no significant relationship between the trees' constitutive palatability and the number of invertebrate herbivore species they support, this previously-demonstrated relationship closely approached significance when the species showing wound-induced effects were excluded from the regression. These results are discussed within the limitations of laboratory bioassays and the possible field consequences are briefly considered.

The effect of mollusc grazing on seedling recruitment in artificially created grassland gaps.

Two experiments conducted in spring and autumn 1992 examined the effect of mollusc grazing on seedling regeneration from natural grassland seedbanks by creating artificial gaps in plots in a grassland sward. Molluscs were excluded from half the gaps by application of molluscicide. Mollusc grazing in both the spring and autumn experiment significantly reduced seedling recruitment, though the intensity of grazing was greatest in autumn. Recruitment of five species was markedly influenced by molluscicide application. In spring, plots from which molluscs were excluded contained significantly more seedlings of Chenopodium polyspermum and Ranunculus acris. In the autumn, exclusion of molluscs resulted in increased populations of R. acris, Stellaria graminea and Rumex acetosa. Cerastium holosteoides populations were greatest in autumn grazed plots. Other species, notably the grasses Holcus lanatus and Agrostis capillaris and the legume Trifolium repens were unaffected by molluscicide application. Species diversity was significantly decreased by molluscicide application in the autumn. Gap size significantly affected the recruitment of two species. Ranunculus acris populations were significantly higher in small gaps in both spring and summer, while Chenopodium recruitment in the spring was greater in small gaps. Gap size also significantly influenced the risk of mollusc attack on Ranunculus as molluscs appeared to show an aggregative feeding response in the high seedling density small gaps. Selective grazing of vulnerable seedlings by molluscs may influence the eventual relative proportions of the species present and so provide a potent mechanism in shaping community composition in grasslands.

Wound-induced changes in the palatability of Betula pubescens and B. pendula.

Leaves of Betula were damaged artificially in April, June and August 1982. Palatability of damaged and adjacent undamaged leaves was assessed against controls in bioassays using the polyphagous Lepidoptera Spodoptera littoralis and Orgyia antiqua. Assessments were carried out at intervals from six hours to five months following each damage date. Palatability (relative proportions of leaves consumed) was significantly lower than controls in damaged and adjacent leaves after six hours and remained detectable for up to two months but this was less clear in the June-damaged samples and undetectable in the August group. Adjacent leaves were significantly affected whether distal or proximal to the damaged leaves. Marked and significant changes occurred in levels of soluble tannins in the damaged and adjacent leaves but the relationship between crude tannin levels and changed palatability was not simple cause and effect. No significant effects of damage on aphid (Euceraphis punctipennis) reproduction could be detected among birches in a growth room experiment in which half the trees were artificially damaged and half were controls. The results are discussed in the light of earlier work on induced defence in birch and five areas of significant new information represented by the results in this paper are identified.

Wound-induced changes in tomato leaves and their effects on the feeding patterns of larval lepidoptera.

Several studies have shown changes in the patterns of damage from feeding insects associated with changes in palatability and overall consumption as a result of wound-induced chemical changes in plants. This paper describes how the pattern of feeding damage made by the larvae of Spodoptera littoralis Boisd. (Lepidoptera: Noctuidae) on tomato is affected by changes in palatability of the leaves. Two sorts of responses to leaves from plants that had received prior damage were observed. Larvae offered a choice of leaves tended to take fewer meals on leaves from previously-wounded plants than on control leaves, frequently rejecting the former after sampling them. On wounded plants this rejection behaviour was associated with a shift in feeding site towards the base of the plant. However, starved larvae offered only a single excised leaf readily ate leaves from wounded plants but took shorter meals on these leaves than on controls. Although it was not directly tested it is possible that this difference in response reflected changes in food selectivity with a differing level of satiation. The results are considered in relation to the adaptive significance of the plant of changes in within-plant distributions of herbivore damage.