Towards a standardization of non-symbolic numerical experiments: GeNEsIS, a flexible and user-friendly tool to generate controlled stimuli.

Several studies have suggested that vertebrate and invertebrate species may possess a number sense, i.e. an ability to process in a non-symbolic and non-verbal way the numerousness of a set of items. However, this hypothesis has been challenged by the presence of other non-numerical continuous physical variables, which vary along with numerosity (i.e., any change in the number of visual physical elements in a set naturally involves a related change in visual features such as area, density, contour length and convex hull of the stimulus). It is therefore necessary to control and manipulate the continuous physical information when investigating the ability of humans and other animals to perceive numerousness. During decades of research, different methods have been implemented in order to address this issue, which has implications for experiment replicability and inter-species comparisons, since no general standardized procedure is currently being used. Here we present the 'Generation of Numerical Elements Images Software' (GeNEsIS) for the creation of non-symbolic numerical arrays in a standardized and user-friendly environment. The main aim of this tool is to provide researchers in the field of numerical cognition a manageable and precise instrument to produce visual numerical arrays controlled for all the continuous variables. Additionally, we implemented the ability to actively guide stimuli presentation during habituation/dishabituation and dual-choice comparison tasks used in human and comparative research.

A sense of number in invertebrates.

Non-symbolic numerical abilities are widespread among vertebrates due to their important adaptive value. Moreover, these abilities were considered peculiar of vertebrate species as numerical competence is regarded as cognitively sophisticated. However, recent evidence convincingly showed that this is not the case: invertebrates, with their limited number of neurons, proved able to successfully discriminate different quantities (e.g., of prey), to use the ordinal property of numbers, to solve arithmetic operations as addition and subtraction and even to master the concept of zero numerosity. To date, though, the debate is still open on the presence and the nature of a «sense of number¼ in invertebrates. Whether this is peculiar for discrete countable quantities (numerosities) or whether this is part of a more general magnitude system dealing with both discrete and continuous quantities, as hypothesized for humans and other vertebrates. Here we reviewed the main studies on numerical abilities of invertebrates, discussing in particular the recent findings supporting the hypothesis of a general mechanism that allows for processing of both discrete (i.e., number) and continuous dimensions (e.g., space).

Turbulent Flow Promotes Cleavage of VWF (von Willebrand Factor) by ADAMTS13 (A Disintegrin and Metalloproteinase With a Thrombospondin Type-1 Motif, Member 13).

Objective- Acquired von Willebrand syndrome is defined by excessive cleavage of the VWF (von Willebrand Factor) and is associated with impaired primary hemostasis and severe bleeding. It often develops when blood is exposed to nonphysiological flow such as in aortic stenosis or mechanical circulatory support. We evaluated the role of laminar, transitional, and turbulent flow on VWF cleavage and the effects on VWF function. Approach and Results- We used a vane rheometer to generate laminar, transitional, and turbulent flow and evaluate the effect of each on VWF cleavage in the presence of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif, member 13). We performed functional assays to evaluate the effect of these flows on VWF structure and function. Computational fluid dynamics was used to estimate the flow fields and forces within the vane rheometer under each flow condition. Turbulent flow is required for excessive cleavage of VWF in an ADAMTS13-dependent manner. The assay was repeated with whole blood, and the turbulent flow had the same effect. Our computational fluid dynamics results show that under turbulent conditions, the Kolmogorov scale approaches the size of VWF. Finally, cleavage of VWF in this study has functional consequences under flow as the resulting VWF has decreased ability to bind platelets and collagen. Conclusions- Turbulent flow mediates VWF cleavage in the presence of ADAMTS13, decreasing the ability of VWF to sustain platelet adhesion. These findings impact the design of mechanical circulatory support devices and are relevant to pathological environments where turbulence is added to circulation.

Honeybees use absolute rather than relative numerosity in number discrimination.

Various vertebrate species use relative numerosity judgements in comparative assessments of quantities for which they use larger/smaller relationships rather than absolute number. The numerical ability of honeybees shares basic properties with that of vertebrates but their use of absolute or relative numerosity has not been explored. We trained free-flying bees to choose variable images containing three dots; one group ('larger') was trained to discriminate 3 from 2, while another group ('smaller') was trained to discriminate 3 from 4. In both cases, numbers were kept constant but stimulus characteristics and position were varied from trial to trial. Bees were then tested with novel stimuli displaying the previously trained numerosity (3) versus a novel numerosity (4 for 'larger' and 2 for 'smaller'). Both groups preferred the three-item stimulus, consistent with absolute numerosity. They also exhibited ratio-dependent discrimination of numbers, a property shared by vertebrates, as performance after 2 versus 3 was better than after 3 versus 4 training. Thus, bees differ from vertebrates in their use of absolute rather than of relative numerosity but they also have some numeric properties in common.

Hemolysis generation from a novel, linear positive displacement blood pump for cardiopulmonary bypass on a six kilogram piglet: a preliminary report.

BACKGROUND: Current blood pumps used for cardiopulmonary bypass generally fall into two different pump design categories; non-occlusive centrifugal pumps and occlusive, positive-displacement roller pumps. The amount of foreign surface area of extracorporeal circuits correlates with post-operative morbidity due to systemic inflammation, leading to a push for technology that reduces the amount of foreign surfaces. Current roller pumps are bulky and the tubing forms an arc in the pumping chamber (raceway), positioning the inlet 360 degrees from the outlet, making it very difficult to place the pump closer to the patient and to efficiently reduce tubing length. These challenges put existing roller pumps at a disadvantage for use in a compact cardiopulmonary bypass circuit. Centrifugal blood pumps are easier to incorporate into miniature circuit designs. However, the prime volumes of current centrifugal pump designs are large, especially for pediatric extracorporeal circuits where the prime volumes are too great to be of clinical value. METHOD: We describe a preliminary report on a novel, occlusive, linear, single-helix, positive-displacement blood pump which allows for decreased prime volume and surface area of the extracorporeal circuit. This new experimental pump design was used to perfuse a 6 kilogram piglet with a pediatric cardiopulmonary bypass circuit for two hours of continuous use. Blood samples were obtained every thirty minutes and assayed for plasma free hemolysis generation. CONCLUSIONS: The results from this initial experiment showed low plasma free hemoglobin generation and encourages the authors to further develop this concept.

Transfer from continuous to discrete quantities in honeybees.

Honeybees can estimate quantities having different dimensions: continuous and uncountable such as the relative size of visual objects in an array, or discrete and countable such as the number of objects of the array. Honeybees can transfer quantity discrimination (i.e., choosing the larger/smaller stimulus) from number to size. Here, we investigated whether honeybees could also generalize from the size (continuous) to the number (discrete) dimension. We trained free-flying foragers to discriminate between large- and small-size elements. At test, bees were presented with a comparison between larger and smaller numerosities controlled for different continuous variables covarying with numerosity such as total area, total perimeter, convex hull, and element size. Results showed that bees generalized from the size to the numerical dimension of the stimuli. This cross-dimensional transfer supports the idea of a universal mechanism for the encoding of abstract magnitudes in invertebrate species comparable to that of vertebrate species.

Transfer from Number to Size Reveals Abstract Coding of Magnitude in Honeybees.

Number discrimination has been documented in honeybees. It is not known, however, whether it reflects, as in vertebrates, the operating of an underlying general magnitude system that estimates quantities irrespective of dimensions (e.g., number, space, time) and format (discrete, continuous). We trained bees to discriminate between different numerical comparisons having either a 0.5 (2 versus 4; 4 versus 8) or 0.67 ratio (2 versus 3; 4 versus 6). Bees were then tested for spontaneous choice using comparisons with identical numbers but different sizes. Irrespective of the ratio of stimuli, bees trained to select the smaller numerical quantity chose the congruent smaller size; bees trained to select the larger numerical quantity chose the congruent larger size. This finding provides the evidence for a cross-dimensional transfer between discrete (numerical) and continuous (spatial) dimensions in an invertebrate species and supports the hypothesis of a cognitive universality of a coding for general magnitude.

Pathologic Shear and Elongation Rates Do Not Cause Cleavage of Von Willebrand Factor by ADAMTS13 in a Purified System.

INTRODUCTION: Pathological flows in patients with severe aortic stenosis are associated with acquired von Willebrand syndrome. This syndrome is characterized by excessive cleavage of von Willebrand factor by its main protease, A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13 (ADAMTS13) leading to decreased VWF function and mucocutaneous bleeding. Aortic valve replacement and correction of the flow behavior to physiological levels reverses the syndrome, supporting the association between pathological flow and acquired von Willebrand syndrome. We investigated the effects of shear and elongational rates on von Willebrand factor cleavage in the presence of ADAMTS13. METHODS: We identified acquired von Willebrand syndrome in five patients with severe aortic stenosis. Doppler echography values from these patients were used to develop three computational fluid dynamic (CFD) aortic valve models (normal, mild and severe stenosis). Shear, elongational rates and exposure times identified in the CFD simulations were used as parameters for the design of microfluidic devices to test the effects of pathologic shear and elongational rates on the structure and function of von Willebrand factor. RESULTS: The shear rates (0-10,000s-1), elongational rates (0-1000 s-1) and exposure times (1-180 ms) tested in our microfluidic designs mimicked the flow features identified in patients with aortic stenosis. The shear and elongational rates tested in vitro did not lead to excessive cleavage or decreased function of von Willebrand factor in the presence of the protease. CONCLUSIONS: High shear and elongational rates in the presence of ADAMTS13 are not sufficient for excessive cleavage of von Willebrand Factor.

A mathematical model of coagulation under flow identifies factor V as a modifier of thrombin generation in hemophilia A.

BACKGROUND: The variability in bleeding patterns among individuals with hemophilia A, who have similar factor VIII (FVIII) levels, is significant and the origins are unknown. OBJECTIVE: To use a previously validated mathematical model of flow-mediated coagulation as a screening tool to identify parameters that are most likely to enhance thrombin generation in the context of FVIII deficiency. METHODS: We performed a global sensitivity analysis (GSA) on our mathematical model to identify potential modifiers of thrombin generation. Candidates from the GSA were confirmed by calibrated automated thrombography (CAT) and flow assays on collagen-tissue factor (TF) surfaces at a shear rate of 100 per second. RESULTS: Simulations identified low-normal factor V (FV) (50%) as the strongest modifier, with additional thrombin enhancement when combined with high-normal prothrombin (150%). Low-normal FV levels or partial FV inhibition (60% activity) augmented thrombin generation in FVIII-inhibited or FVIII-deficient plasma in CAT. Partial FV inhibition (60%) boosted fibrin deposition in flow assays performed with whole blood from individuals with mild and moderate FVIII deficiencies. These effects were amplified by high-normal prothrombin levels in both experimental models. CONCLUSIONS: These results show that low-normal FV levels can enhance thrombin generation in hemophilia A. Further explorations with the mathematical model suggest a potential mechanism: lowering FV reduces competition between FV and FVIII for factor Xa (FXa) on activated platelet surfaces (APS), which enhances FVIII activation and rescues thrombin generation in FVIII-deficient blood.

Quaternized Q-PEIPAAm-Based Antimicrobial Reverse Thermal Gel: A Potential for Surgical Incision Drapes.

A quaternized reverse thermal gel (RTG) aimed at replacing current surgical incision drapes (SIDs) was designed and characterized. The antimicrobial efficacy of the quaternized RTG was analyzed using both in vitro and in vivo models and was compared to standard SIDs. Polymer characterization was completed using both nuclear magnetic resonance (1H NMR) and lower critical solution temperature (LCST) analysis. Biocompatibility was assessed using a standard cell viability assay. The in vitro antimicrobial efficacy of the polymer was analyzed against four common bacteria species using a time-kill test. The in vivo antimicrobial efficacy of the polymer and standard SIDs were compared using a murine model aimed at mimicking surgical conditions. NMR confirmed the polymer structure and presence of quaternized groups and alkyl chains. The polymer displayed a LCST of 34 °C and a rapid rate of gelation, allowing stable gel formation when applied to skin. Once quaternized, the polymer displayed an increase in kill-rate of bacteria compared to unquaternized polymer. In experiments aimed at mimicking surgical conditions, the quaternized polymer showed statistically comparable bacteria-killing capacity to the standard SID and even surpassed the SID for killing capacity at various time points. A novel approach to replacing current SIDs was developed using an antimicrobial polymer system with RTG properties. The RTG properties of this polymer maintain a liquid state at low temperatures and a gel upon heating, allowing this polymer to form a tight coating when applied to skin. Furthermore, this polymer achieved excellent antimicrobial properties in both in vitro and in vivo models. With further optimization, this polymer system has the potential to replace and streamline presurgical patient preparations through its easy application and beneficial antimicrobial properties.