Toward Engineering Biosystems With Emergent Collective Functions.

Many complex behaviors in biological systems emerge from large populations of interacting molecules or cells, generating functions that go beyond the capabilities of the individual parts. Such collective phenomena are of great interest to bioengineers due to their robustness and scalability. However, engineering emergent collective functions is difficult because they arise as a consequence of complex multi-level feedback, which often spans many length-scales. Here, we present a perspective on how some of these challenges could be overcome by using multi-agent modeling as a design framework within synthetic biology. Using case studies covering the construction of synthetic ecologies to biological computation and synthetic cellularity, we show how multi-agent modeling can capture the core features of complex multi-scale systems and provide novel insights into the underlying mechanisms which guide emergent functionalities across scales. The ability to unravel design rules underpinning these behaviors offers a means to take synthetic biology beyond single molecules or cells and toward the creation of systems with functions that can only emerge from collectives at multiple scales.

VO2, Liking, and Relative Reinforcing Value of Cooperative and Competitive Exergame Play in Young Children.

The purpose of the current study was to examine physiologic response, liking, and relative reinforcing value (RRV) of children playing an exergame with a friend under two goal structures: competitive and cooperative. A sample of twenty participants (8.7 ± 1.3 years old) and a self-selected friend completed three conditions: rest, competitive, and cooperative play. During the competitive condition, participants played Nintendo Wii Tennis® against their friend. During cooperative play, participants and their friend played together against a computer avatar. During each condition, oxygen consumption (VO2, ml·kg-1·min-1) and liking (visual analog scale) were recorded. After finishing all conditions, children completed an RRV computer task to assess their motivation to play the competitive versus cooperative goal structures. During this task children performed work (button presses) to participate in additional competitive play, cooperative play, or a combination. The output maximum (Omax), or maximum work for each goal structure, was used as the measure of RRV. It was determined that VO2 was significantly (p ≤ 0.001) greater for cooperative and competitive play than rest. Liking was significantly greater for cooperative play than rest (p ≤ 0.001) and competitive play (p = 0.03). There were no significant differences (p > 0.05) between cooperative and competitive play for VO2 or Omax. In conclusion, while liking was greater for the cooperative condition versus competitive, motivation did not differ between goal structures. Further investigation into methods of making physical activity more reinforcing, in addition to well-liked by children, is necessary to optimize this behavior.

Easybiotics: a GUI for 3D physical modelling of multi-species bacterial populations.

MOTIVATION: 3D physical modelling is a powerful computational technique that allows for the simulation of complex systems such as consortia of mixed bacterial species. The complexities in physical modelling reside in the knowledge intensive model building process and the computational expense in calculating their numerical solutions. These models can offer insights into microbiology, both in understanding natural systems and as design tools for developing novel synthetic bacterial systems. Developing a robust synthetic system typically requires multiple iterations around the specify→design→build→test cycle to meet specifications. This process is laborious and expensive for both the computational and laboratory aspects, hence any improvement in any of the workflow steps would be welcomed. We have previously introduced Simbiotics, a powerful and flexible platform for designing and analyzing 3D simulations of mixed species bacterial populations. Simbiotics requires programming experience to use which creates barriers to entry for use of the tool. RESULTS: In the spirit of enabling biologists who may not have programming skills to install and utilize Simbiotics, we present in this application note Easybiotics, a user-friendly graphical user interface for Simbiotics. Users may design, simulate and analyze models from within the graphical user interface, with features such as live graph plotting and parameter sweeps. Easybiotics provides full access to all of Simbiotics simulation features, such as cell growth, motility and gene regulation. AVAILABILITY AND IMPLEMENTATION: Easybiotics and Simbiotics are free to use under the GPL3.0 licence, and can be found at: http://ico2s.org/software/simbiotics.html. We also provide readily downloadable virtual machine sandboxes to facilitate rapid installation.

Aeromedical Transfer of Patients with Viral Hemorrhagic Fever.

For >40 years, the British Royal Air Force has maintained an aeromedical evacuation facility, the Deployable Air Isolator Team (DAIT), to transport patients with possible or confirmed highly infectious diseases to the United Kingdom. Since 2012, the DAIT, a joint Department of Health and Ministry of Defence asset, has successfully transferred 1 case-patient with Crimean-Congo hemorrhagic fever, 5 case-patients with Ebola virus disease, and 5 case-patients with high-risk Ebola virus exposure. Currently, no UK-published guidelines exist on how to transfer such patients. Here we describe the DAIT procedures from collection at point of illness or exposure to delivery into a dedicated specialist center. We provide illustrations of the challenges faced and, where appropriate, the enhancements made to the process over time.

Population Dynamics of Autocatalytic Sets in a Compartmentalized Spatial World.

Autocatalytic sets are self-sustaining and collectively catalytic chemical reaction networks which are believed to have played an important role in the origin of life. Simulation studies have shown that autocatalytic sets are, in principle, evolvable if multiple autocatalytic subsets can exist in different combinations within compartments, i.e., so-called protocells. However, these previous studies have so far not explicitly modeled the emergence and dynamics of autocatalytic sets in populations of compartments in a spatial environment. Here, we use a recently developed software tool to simulate exactly this scenario, as an important first step towards more realistic simulations and experiments on autocatalytic sets in protocells.

Simbiotics: A Multiscale Integrative Platform for 3D Modeling of Bacterial Populations.

Simbiotics is a spatially explicit multiscale modeling platform for the design, simulation and analysis of bacterial populations. Systems ranging from planktonic cells and colonies, to biofilm formation and development may be modeled. Representation of biological systems in Simbiotics is flexible, and user-defined processes may be in a variety of forms depending on desired model abstraction. Simbiotics provides a library of modules such as cell geometries, physical force dynamics, genetic circuits, metabolic pathways, chemical diffusion and cell interactions. Model defined processes are integrated and scheduled for parallel multithread and multi-CPU execution. A virtual lab provides the modeler with analysis modules and some simulated lab equipment, enabling automation of sample interaction and data collection. An extendable and modular framework allows for the platform to be updated as novel models of bacteria are developed, coupled with an intuitive user interface to allow for model definitions with minimal programming experience. Simbiotics can integrate existing standards such as SBML, and process microscopy images to initialize the 3D spatial configuration of bacteria consortia. Two case studies, used to illustrate the platform flexibility, focus on the physical properties of the biosystems modeled. These pilot case studies demonstrate Simbiotics versatility in modeling and analysis of natural systems and as a CAD tool for synthetic biology.

The effect of a peer on VO2 and game choice in 6-10 year old children.

UNLABELLED: Relative to sedentary video games (e.g., Playstation 2®), playing physically active video games (e.g., Nintendo Wii Sports Boxing®) significantly increases caloric expenditure in children. Studies have demonstrated that the presence of a peer increases physical activity in children. We sought to determine if children would expend more energy and find playing the "exergame" (Wii) more motivating than the sedentary video game (Playstation 2) when with a peer. Seventeen children (age 8.5 ± 0.4 years) rested, played the sedentary video game and "exergame" for 10 min each, in two conditions: one in which the children rested/played the games alone (alone condition) and another in which they played with a peer (peer condition). Oxygen consumption (VO2), and liking (visual analog scale) was assessed for each 10-min condition. After three 10-min resting/gaming conditions, motivation was assessed using a relative reinforcing value task in which children performed computer mouse presses to gain additional access for either the sedentary video game or "exergame." VO2 was greater (p < 0.001) during "exergame" play (mean = 12.17 ± 4.1 ml·kg(-1)·min(-1)) vs. rest (mean = 5.14 ± 1.46 ml·kg(-1)·min(-1)) and the sedentary video game (mean = 5.83 ± 2.1 ml·kg(-1)·min(-1)). During the peer condition, there were no significant differences (p > 0.05) in VO2 relative to the alone condition. In an exploratory analysis boys exhibited a greater (p = 0.02) increase in VO2 from rest to "exergame" (Δ 9.0 ± 3.7 ml·kg(-1)·min(-1)), relative to girls (Δ 4.9 ± 2.9 ml·kg(-1)·min(-1)). Boys showed a significantly greater increase (p = 0.05) in VO2 from the resting condition to "exergame" in the presence of a peer (Δ 11.1 ± 5.3 ml·kg(-1)·min(-1)) vs. the alone condition (Δ 6.8 ± 3.1 ml·kg(-1) ·min(-1)). Liking was significantly (p < 0.001) greater for "exergame" (7.7 ± 1.9 cm) and the sedentary video game (8.3 ± 1.3 cm) relative to rest (4.0 ± 2.8 cm). Motivation for "exergame" significantly decreased (p = 0.03) from alone (340.8 ± 106.8 presses) to the peer condition (147.8 ± 81.6 presses). CONCLUSION: VO2 was greater during "exergame" play relative to the sedentary video game. The presence of a peer did not increase VO2 during "exergame" play. Surprisingly, the presence of a peer decreased children's motivation to play "exergame" vs. the sedentary video game.

Preparing students for careers in food-supply veterinary medicine: a review of educational programs in the United States.

The real and/or perceived shortage of veterinarians serving food-supply veterinary medicine has been a topic of considerable discussion for decades. Regardless of this debate, there are issues still facing colleges of veterinary medicine (CVMs) about the best process of educating future food-supply veterinarians. Over the past several years, there have been increasing concerns by some that the needs of food-supply veterinary medicine have not adequately been met through veterinary educational institutions. The food-supply veterinary medical curriculum offered by individual CVMs varies depending on individual curricular design, available resident animal population, available food-animal caseload, faculty, and individual teaching efforts of faculty. All of the institutional members of the Association of American Veterinary Medical Colleges (AAVMC) were requested to share their Food Animal Veterinary Career Incentives Programs. The AAVMC asked all member institutions what incentives they used to attract and educate students interested in, or possibly considering, a career in food-supply veterinary medicine (FSVM). The problem arises as to how we continue to educate veterinary students with ever shrinking budgets and how to recruit and retain faculty with expertise to address the needs of society. Several CVMs use innovative training initiatives to help build successful FSVM programs. This article focuses on dairy, beef, and swine food-animal education and does not characterize colleges' educational efforts in poultry and aquaculture. This review highlights the individual strategies used by the CVMs in the United States.

Infusion of sodium bicarbonate in experimentally induced metabolic acidosis does not provoke cerebrospinal fluid (CSF) acidosis in calves.

In a crossover study, 5 calves were made acidotic by intermittent intravenous infusion of isotonic hydrochloric acid (HCl) over approximately 24 h. This was followed by rapid (4 h) or slow (24 h) correction of blood pH with isotonic sodium bicarbonate (NaHCO(3)) to determine if rapid correction of acidemia produced paradoxical cerebrospinal fluid (CSF) acidosis. Infusion of HCl produced a marked metabolic acidosis with respiratory compensation. Venous blood pH (mean ± S(x)) was 7.362 ± 0.021 and 7.116 ± 0.032, partial pressure of carbon dioxide (Pco(2), torr) 48.8 ± 1.3 and 34.8 ± 1.4, and bicarbonate (mmol/L), 27.2 ± 1.27 and 11 ± 0.96; CSF pH was 7.344 ± 0.031 and 7.240 ± 0.039, Pco(2) 42.8 ± 2.9 and 34.5 ± 1.4, and bicarbonate 23.5 ± 0.91 and 14.2 ± 1.09 for the period before the infusion of hydrochloric acid and immediately before the start of sodium bicarbonate correction, respectively. In calves treated with rapid infusion of sodium bicarbonate, correction of venous acidemia was significantly more rapid and increases in Pco(2) and bicarbonate in CSF were also more rapid. However, there was no significant difference in CSF pH. After 4 h of correction, CSF pH was 7.238 ± 0.040 and 7.256 ± 0.050, Pco(2) 44.4 ± 2.2 and 34.2 ± 2.1, and bicarbonate 17.8 ± 1.02 and 14.6 ± 1.4 for rapid and slow correction, respectively. Under the conditions of this experiment, rapid correction of acidemia did not provoke paradoxical CSF acidosis.

Factors affecting rectal temperature measurement using commonly available digital thermometers.

Rectal temperature measurement is an essential part of physical examination of cattle and some physiological experiments. Modern digital thermometers are often used to measure rectal temperatures by students; this study describes their reliability and appropriate use. Students measured rectal temperature on 53 occasions using their personal digital thermometer and techniques gained from previous instruction, rectal temperature was also measured by an experienced person using a Cornell mercury thermometer completely inserted in the rectum. Cornell mercury thermometers values were 38.95±0.05°C (mean±1 SE, n=53). Student rectal temperature measurements using their initial technique were nearly 0.5°C lower, 38.46±0.07°C. After receiving instruction to insert the digital thermometer to the window, student obtained values were 38.77±0.06°C; these are significantly higher than with the student's initial technique and closer to those obtained with a Cornell thermometer. In a series of 53 water bath tests, student owned thermometers recorded similar mean values to those of a traceable (reference) digital thermometer, Cornell mercury thermometer readings were 0.2°C higher. 10 individual digital thermometers were repeatedly tested against a traceable thermometer in a water bath, one was inaccurate. In a separate experiment a trained clinician tested the effect of angle of insertion of a digital thermometer on temperature readings and the affect was <0.1°C. We conclude that accurate temperature measurements using digital thermometers are only likely if the thermometer is inserted to the beginning of the window and the thermometer's accuracy is checked periodically.

Demographic survey of veterinarians employed in western Canada.

The objective of this study was to generate demographic data on veterinarians working in western Canada. A sample of 551 veterinarians was randomly selected from a population of 2474 veterinarians employed in western Canada, 425 (77.1%) of whom responded to the survey. The respondents were evenly split between males (53.1%) and females (46.9%). More than half (58.0%) of the private practitioners practised exclusively on companion animals (small animals and horses), while 2.9% devoted 100% of their time to food animals. There were 351 respondents who had had > or = 2 employers since graduation; 80% of those who had begun their careers in companion animal (CA) practice had remained in this type of practice, while 54.3% of those who had begun their careers in mixed animal practice had switched to CA practice. Analyses of wage and workload data from 85 full-time veterinary employees showed that CA practitioners worked the fewest hours/week (47.0), had the least number of evenings on-call/month (3.7), and earned the highest hourly wage (35.79 dollars) as compared with non-CA practitioners.

Factors associated with the career path choices of veterinarians in western Canada.

This second of 2 articles, relating to the veterinary profession in western Canada, explores the factors associated with veterinarians' career path choices. Among other factors, companion animal (small animal and equine) (CA) practitioners were less likely to have been raised in, or near to, a small center (< or = 10 000), were more concerned with their workload (hours of work and number of nights on-call), and preferred to work in progressive practices. Food animal (FA) practitioners were more likely to be male, have been raised in a small center, have been raised in the Province of Saskatchewan, and to have self-assessed themselves as having an above average knowledge of agriculture at the time they applied for admission to veterinary college. Mixed animal (MA) practitioners had more factors in common with FA than with CA practitioners. Three main factors were associated with leaving mixed or food animal practice: hours of work and too many nights on-call, the level of remuneration, and lack of support and mentorship.

A comparison of objective and subjective measures of cough in asthma.

BACKGROUND: Cough is widely recognized as a key symptom in the diagnosis and the monitoring of asthma, but little is known about how best to assess cough in asthma. OBJECTIVE: To determine how objective cough rates correlate with subjective measures of cough in asthma. METHODS: We studied 56 subjects, median age 42.0 years (range, 28.5-71), 34 (60.7%) female, with asthma. Subjects performed cough reflex sensitivity testing (concentration of citric acid causing 2 and 5 coughs [C2 and C5]), 24-hour fully ambulatory cough recordings, subjectively scored the severity of their cough (visual analog scales and 0-5 score) and completed a cough-related quality of life questionnaire (Leicester Cough Questionnaire). Ambulatory cough recordings were manually counted and reported in cough seconds per hour (cs/h). RESULTS: The median time spent coughing was 2.6 cs/h (range, 0.0-14.2), with subjects spending more time coughing by day (median, 3.9 cs/h [0.0-18.5]) than by night (median, 0.3 cs/h [0.0-8.7]; P < .001). A weak inverse relationship was seen between day cough rates and log(10)C2 (r = -0.39; P = .03) but not log(10)C5 (r = -0.08; P = .65). Objective time spent coughing was also weak-moderately associated with subjective cough scores and visual analog scales, and most strongly correlated with cough-related quality of life (r = -0.54; P < .001). CONCLUSION: Subjective measures of cough and cough reflex sensitivity are poor surrogates for objective cough frequency in asthma. When designing studies to assess interventions for cough in asthma, we advocate a combination of both objective measures of cough and cough-related quality of life.

Factors affecting the career path choices of graduates at the Western College of Veterinary Medicine.

The objective of this study was to describe the demographics of the Class of 2006, Western College of Veterinary Medicine, and to determine which factors influenced the graduates' career path choices. Data were collected via an on-line survey and the response rate was 95.7% (67/70). The majority (57%) of graduates were starting their veterinary career in a food animal-related (FAR) job. Two factors were significantly associated with this choice: 1) those raised in, or near, a small center (population < 10 000) were 3.4 times (P = 0.03) more likely to accept a FAR position than were those raised in a large center (> 10 000), and 2) graduates with a bachelor of science in agriculture (BSc Ag) were 4.5 times (P = 0.04) more likely to begin their career as a FAR practitioner than were those without such a degree. However, 9 of the 16 graduates having a BSc Ag had an urban upbringing.

D-Lactic acid-induced neurotoxicity in a calf model.

Lactic acidosis (DAC) occurs as a complication of short-bowel syndrome in humans and in a variety of other gastrointestinal disorders in monogastrics and ruminants. DAC is associated with signs of impaired central nervous system (CNS) function including ataxia and coma. The objective of this experiment was to determine whether either acidification of nervous tissue or d-lactic acid is responsible for decreased neurological function. Eight Holstein calves (32 +/- 11 days, 70 +/- 10 kg) were surgically catheterized with indwelling intravenous jugular and atlanto-occipital space cerebrospinal fluid (CSF) catheters and infused for 6 h in random order with isomolar dl-lactic acid (dl-LA), l-lactic acid (l-LA), hydrochloric acid (HCl), or saline. dl-LA induced ataxia after 4 h of infusion and produced the greatest obtunding of CNS function (at 7 h, score 8.0 +/- 0.4), whereas the other infusions caused neither ataxia nor scores over 1.5 (P < 0.01 from dl-LA). dl-LA induced significantly less acidemia than HCl (at 6 h pH 7.13 +/- 0.06 and 7.00 +/- 0.04, base excess -16 +/- 1 and -23 +/- 3 mmol/l, bicarbonate 11 +/- 1 and 8 +/- 1 mmol/l respectively, all P < 0.01) but greater than l-LA and saline (P < 0.01). CSF changes followed a similar but less pronounced pattern. Although HCl infusion produced a severe acidemia and CSF acidosis, only minor effects on neurological function were evident suggesting that d-lactate has a direct neurotoxic effect that is independent of acidosis. Conversely, l-LA produced only minor neurological changes.

The effects of feeding and fasting on gastrointestinal sounds in adult horses.

The effect of changes in feed intake on auscultatable gastrointestinal sounds has not been systematically studied. Disagreement also is present in the literature about variation in sounds according to the quadrant of auscultation. Gastrointestinal sounds were recorded over the center of the left dorsal, left ventral, right ventral, and right dorsal quadrants and over the middle of the right abdominal flank. During 24 hours (n = 4) or 48 hours (n = 5) of fasting, there was a reduction in the intensity of gastrointestinal sounds as assessed by analysis of sound recordings. There was also a reduction in the number of mixing-like and propulsive-like sounds heard by 2 blinded observers. After refeeding, there was a marked increase in sound. Sound intensity varied among abdominal quadrants, but blinded observers did not notice significant differences in the number of mixing-like sounds. The left dorsal quadrant was quieter than others during fasting and refeeding. The right ventral quadrant appeared to be least affected by fasting, and sounds were louder over the right ventral and right middle quadrants than over the others. The blinded observers' perceptions of sound correlated poorly with one another and with objective measures of sound intensity. This experiment demonstrates the effectiveness of computerized analysis of abdominal sound in detecting a reduction in the intensity of gastrointestinal sounds during fasting and their return during refeeding. The left dorsal quadrant was quieter than other quadrants, likely because of its position over the small colon. There was considerable observer variation in the number of intestinal sounds heard.

Obstruction of the small intestine by a trichobezoar in cattle: 15 cases (1992-2002).

OBJECTIVE: To determine historical and clinical findings, treatment, and outcome for cattle with small intestinal obstruction caused by a trichobezoar. DESIGN: Retrospective case series. ANIMALS: 15 cattle. PROCEDURES: Medical records of cattle with a diagnosis of small intestinal obstruction by a trichobezoar from 1992 to 2002 were reviewed. Information pertaining to various aspects of diagnosis, treatment, and outcome was collected from records. RESULTS: Trichobezoars were more common in young cattle, and affected cattle did not deteriorate clinically as rapidly as cattle with other types of intestinal obstruction. The most common initial owner complaints included decreased or absent fecal output, inappetance, abdominal distension, and signs of abdominal pain. Common clinical findings were dehydration, decreased or absent rumen motility, signs of depression, splashing sounds during succussion of the abdomen, and a pinging sound on percussion of the abdomen. The jejunum was obstructed in 10 cattle. Hypochloremic metabolic alkalosis and chronic inflammation were common laboratory findings. All 4 cattle that underwent abdominocentesis had peritonitis. The obstructing trichobezoar was removed surgically in 9 cattle, of which 7 survived and 2 died. The 6 cattle treated medically died or were euthanized. CONCLUSIONS AND CLINICAL RELEVANCE: Obstruction of the small intestine by a trichobezoar is uncommon, but it should be considered as a differential diagnosis in cattle with signs of intestinal obstruction, particularly if they are younger than 4 years of age and have a history of nonacute signs of intestinal obstruction. Surgical removal appears to be a favorable method of treatment and should be considered when this condition is suspected.