Behavioural ecology meets oncology: quantifying the recovery of animal behaviour to a transient exposure to a cancer risk factor.

Wildlife is increasingly exposed to sublethal transient cancer risk factors, including mutagenic substances, which activates their anti-cancer defences, promotes tumourigenesis, and may negatively impact populations. Little is known about how exposure to cancer risk factors impacts the behaviour of wildlife. Here, we investigated the effects of a sublethal, short-term exposure to a carcinogen at environmentally relevant concentrations on the activity patterns of wild Girardia tigrina planaria during a two-phase experiment, consisting of a 7-day exposure to cadmium period followed by a 7-day recovery period. To comprehensively explore the effects of the exposure on activity patterns, we employed the double hierarchical generalized linear model framework which explicitly models residual intraindividual variability in addition to the mean and variance of the population. We found that exposed planaria were less active compared to unexposed individuals and were able to recover to pre-exposure activity levels albeit with a reduced variance in activity at the start of the recovery phase. Planaria showing high activity levels were less predictable with larger daily activity variations and higher residual variance. Thus, the shift in behavioural variability induced by an exposure to a cancer risk factor can be quantified using advanced tools from the field of behavioural ecology. This is required to understand how tumourous processes affect the ecology of species.

Maintenance of Behavioral Variation under Predation Risk: Effects on Personality, Plasticity, and Predictability.

AbstractClassic evolutionary theory predicts that predation will shift trait means and erode variance within prey species; however, several studies indicate higher behavioral trait variance and trait integration in high-predation populations. These results come predominately from field-sampled animals comparing low- and high-predation sites and thus cannot isolate the role of predation from other ecological factors, including density effects arising from higher predation. Here, we study the role of predation on behavioral trait (co)variation in experimental populations of guppies (Poecilia reticulata) living with and without a benthic ambush predator (Jaguar cichlid) to better evaluate the role of predation and where density was equalized among replicates twice per year. At 2.5 years after introduction of the predators (∼10 overlapping generations), 40 males were sampled from each of the six replicate populations and extensively assayed for activity rates, water column use, and latency to feed following disturbance. Individual variation was pronounced in both treatments, with substantial individual variation in means, temporal plasticity, and predictability (inverse residual variance). Predators had little effect on mean behavior, although there was some evidence for greater use of the upper water column in predator-exposed fish. There was greater variance among individuals in water column use in predator-exposed fish, and they habituated more quickly over time; individuals higher in the water column fed slower and had a reduced positive correlation with activity, although again this effect was time specific. Predators also affected the integration of personality and plasticity-among-individual variances in water column use increased, and those in activity decreased, through time-which was absent in controls. Our results contrast with the extensive guppy literature showing rapid evolution in trait means, demonstrating either increases or maintenance of behavioral variance under predation.

Peripheral thickening of the sarcomeres and pointed end elongation of the thin filaments are both promoted by SALS and its formin interaction partners.

During striated muscle development the first periodically repeated units appear in the premyofibrils, consisting of immature sarcomeres that must undergo a substantial growth both in length and width, to reach their final size. Here we report that, beyond its well established role in sarcomere elongation, the Sarcomere length short (SALS) protein is involved in Z-disc formation and peripheral growth of the sarcomeres. Our protein localization data and loss-of-function studies in the Drosophila indirect flight muscle strongly suggest that radial growth of the sarcomeres is initiated at the Z-disc. As to thin filament elongation, we used a powerful nanoscopy approach to reveal that SALS is subject to a major conformational change during sarcomere development, which might be critical to stop pointed end elongation in the adult muscles. In addition, we demonstrate that the roles of SALS in sarcomere elongation and radial growth are both dependent on formin type of actin assembly factors. Unexpectedly, when SALS is present in excess amounts, it promotes the formation of actin aggregates highly resembling the ones described in nemaline myopathy patients. Collectively, these findings helped to shed light on the complex mechanisms of SALS during the coordinated elongation and thickening of the sarcomeres, and resulted in the discovery of a potential nemaline myopathy model, suitable for the identification of genetic and small molecule inhibitors.

Reduction of intracellular oxidative stress with a copper-incorporated layered double hydroxide.

Biocompatible Cu(II)-doped layered double hydroxide (CMA) nanoparticles were developed to combat reactive oxygen species. The 2-dimensional nanozymes showed both superoxide dismutase- and catalase-like activities in chemical assays, while proving as efficient antioxidants in the reduction of intracellular oxidative stress. The results indicate the great promise of CMA in antioxidant therapies.

The effect of mitochondrial recombination on fertilization success in blue mussels.

The presence of doubly uniparental inheritance (DUI) in bivalves represents a unique mode of mitochondrial transmission, whereby paternal (male-transmitted M-type) and maternal (female-transmitted F-type) haplotypes are transmitted to offspring separately. Male embryos retain both haplotypes, but the M-type is selectively removed from females. Due to the presence of heteroplasmy in males, mtDNA can recombine resulting in a 'masculinized' haplotype referred to as Mf-type. While mtDNA recombination is usually rare, it has been recorded in multiple mussel species across the Northern Hemisphere. Given that mitochondria are the powerhouse of the cell, different mtDNA haplotypes may have different selective advantages under diverse environmental conditions. This may be particularly important for sperm fitness and fertilization success. In this study we aimed to i) determine the presence, prevalence of the Mf-type in Australian blue mussels (Mytilus sp.) and ii) investigate the effect of Mf-mtDNA on sperm performance (a fitness correlate). We found a high prevalence of recombined mtDNA (≈35 %) located within the control region of the mitochondrial genome, which occurred only in specimens that contained Southern Hemisphere mtDNA. The presence of two female mitotypes were identified in the studied mussels, one likely originating from the Northern Hemisphere, and the other either representing the endemic M. planulatus species or introduced genotypes from the Southern Hemisphere. Despite having recombination events present in a third of the studied population, analysis of sperm performance indicated no difference in fertilization success related to mitotype.

The impact of food availability on tumorigenesis is evolutionarily conserved.

The inability to control cell proliferation results in the formation of tumors in many multicellular lineages. Nonetheless, little is known about the extent of conservation of the biological traits and ecological factors that promote or inhibit tumorigenesis across the metazoan tree. Particularly, changes in food availability have been linked to increased cancer incidence in humans, as an outcome of evolutionary mismatch. Here, we apply evolutionary oncology principles to test whether food availability, regardless of the multicellular lineage considered, has an impact on tumorigenesis. We used two phylogenetically unrelated model systems, the cnidarian Hydra oligactis and the fish Danio rerio, to investigate the impact of resource availability on tumor occurrence and progression. Individuals from healthy and tumor-prone lines were placed on four diets that differed in feeding frequency and quantity. For both models, frequent overfeeding favored tumor emergence, while lean diets appeared more protective. In terms of tumor progression, high food availability promoted it, whereas low resources controlled it, but without having a curative effect. We discuss our results in light of current ideas about the possible conservation of basic processes governing cancer in metazoans (including ancestral life history trade-offs at the cell level) and in the framework of evolutionary medicine.

Time-specific convergence and divergence in individual differences in behavior: Theory, protocols and analyzes.

Over the years, theoreticians and empiricists working in a wide range of disciplines, including physiology, ethology, psychology, and behavioral ecology, have suggested a variety of reasons why individual differences in behavior might change over time, such that different individuals become more similar (convergence) or less similar (divergence) to one another. Virtually none of these investigators have suggested that convergence or divergence will continue forever, instead proposing that these patterns will be restricted to particular periods over the course of a longer study. However, to date, few empiricists have documented time-specific convergence or divergence, in part because the experimental designs and statistical methods suitable for describing these patterns are not widely known. Here, we begin by reviewing an array of influential hypotheses that predict convergence or divergence in individual differences over timescales ranging from minutes to years, and that suggest how and why such patterns are likely to change over time (e.g., divergence followed by maintenance). Then, we describe experimental designs and statistical methods that can be used to determine if (and when) individual differences converged, diverged, or were maintained at the same level at specific periods during a longitudinal study. Finally, we describe why the concepts described herein help explain the discrepancy between what theoreticians and empiricists mean when they describe the "emergence" of individual differences or personality, how they might be used to study situations in which convergence and divergence patterns alternate over time, and how they might be used to study time-specific changes in other attributes of behavior, including individual differences in intraindividual variability (predictability), or genotypic differences in behavior.

The oxoglutarate dehydrogenase complex is involved in myofibril growth and Z-disc assembly in Drosophila.

Myofibrils are long intracellular cables specific to muscles, composed mainly of actin and myosin filaments. The actin and myosin filaments are organized into repeated units called sarcomeres, which form the myofibrils. Muscle contraction is achieved by the simultaneous shortening of sarcomeres, which requires all sarcomeres to be the same size. Muscles have a variety of ways to ensure sarcomere homogeneity. We have previously shown that the controlled oligomerization of Zasp proteins sets the diameter of the myofibril. Here, we looked for Zasp-binding proteins at the Z-disc to identify additional proteins coordinating myofibril growth and assembly. We found that the E1 subunit of the oxoglutarate dehydrogenase complex localizes to both the Z-disc and the mitochondria, and is recruited to the Z-disc by Zasp52. The three subunits of the oxoglutarate dehydrogenase complex are required for myofibril formation. Using super-resolution microscopy, we revealed the overall organization of the complex at the Z-disc. Metabolomics identified an amino acid imbalance affecting protein synthesis as a possible cause of myofibril defects, which is supported by OGDH-dependent localization of ribosomes at the Z-disc.

Infrared flashing light through the cricothyroid membrane as guidance to awake intubation with a flexible bronchoscope: A randomised cross-over study.

BACKGROUND: In case of distorted airway anatomy, awake intubation with a flexible bronchoscope can be extremely difficult or even impossible. To facilitate this demanding procedure, an infrared flashing light source can be placed on the patient's neck superficial to the cricothyroid membrane. The light travels through the skin and tissue to the trachea, from where it can be registered by the advancing bronchoscope in the pharynx and seen as flashing white light on the monitor. We hypothesised that the application of this technique would allow more proximal and easier identification of the correct pathway to the trachea in patients with severe airway pathology. METHODS: As part of awake intubation, patients underwent insertion of a flexible video bronchoscope via the mouth into the trachea. The procedure was performed twice, in random order in each patient, with and without the aid of the transcutaneous flashing infrared light. All insertions were video recorded to determine at which anatomical landmark within the airway the correct pathway was identified. The videos are accessible via this link: https://airwaymanagement.dk/infrared_comparative. The predefined landmarks were in successive order: oral cavity, oro-pharynx, tip of epiglottis, arytenoid cartilages, false cords, vocal cords and trachea, as well as the spaces between them. RESULTS: Twenty-two patients had a total of 44 awake insertions with the flexible bronchoscope. The median anatomical level, at which correct identification of the trachea was obtained on the monitor, was, past the epiglottis, with the conventional technique, and at the level of the oropharynx, when using the infrared flashing light (p = .005). The time until the flashing light or the vocal cords were seen was 21 (22) S, mean (SD), and 48 (62) S, during the insertion with and without infrared flashing light activated, respectively (p = .005). Endoscopists rated it easier (p = .001) to recognise the entrance to the trachea in the infrared-group. CONCLUSION: During awake intubation of patients with airway pathology, the application of trans-cricothyroid infrared flashing light to guide the insertion of a flexible bronchoscope significantly facilitated the recognition of the pathway into the trachea and the correct advancement of the flexible endoscope. REGISTRATION OF CLINICAL TRIAL: NCT03930550.

Practice of oxygen use in anesthesiology - a survey of the European Society of Anaesthesiology and Intensive Care.

BACKGROUND: Oxygen is one of the most commonly used drugs by anesthesiologists. The World Health Organization (WHO) gave recommendations regarding perioperative oxygen administration, but the practice of oxygen use in anesthesia, critical emergency, and intensive care medicine remains unclear. METHODS: We conducted an online survey among members of the European Society of Anaesthesiology and Intensive Care (ESAIC). The questionnaire consisted of 46 queries appraising the perioperative period, emergency medicine and in the intensive care, knowledge about current recommendations by the WHO, oxygen toxicity, and devices for supplemental oxygen therapy. RESULTS: Seven hundred ninety-eight ESAIC members (2.1% of all ESAIC members) completed the survey. Most respondents were board-certified and worked in hospitals with > 500 beds. The majority affirmed that they do not use specific protocols for oxygen administration. WHO recommendations are unknown to 42% of respondents, known but not followed by 14%, and known and followed by 24% of them. Respondents prefer inspiratory oxygen fraction (FiO2) ≥80% during induction and emergence from anesthesia, but intraoperatively < 60% for maintenance, and higher FiO2 in patients with diseased than non-diseased lungs. Postoperative oxygen therapy is prescribed more commonly according to peripheral oxygen saturation (SpO2), but shortage of devices still limits monitoring. When monitoring is used, SpO2 ≤ 95% is often targeted. In critical emergency medicine, oxygen is used frequently in patients aged ≥80 years, or presenting with respiratory distress, chronic obstructive pulmonary disease, myocardial infarction, and stroke. In the intensive care unit, oxygen is mostly targeted at 96%, especially in patients with pulmonary diseases. CONCLUSIONS: The current practice of perioperative oxygen therapy among respondents does not follow WHO recommendations or current evidence, and access to postoperative monitoring devices impairs the individualization of oxygen therapy. Further research and additional teaching about use of oxygen are necessary.

Understanding hesitancy with revealed preferences across COVID-19 vaccine types.

Many countries have secured larger quantities of COVID-19 vaccines than their population is willing to take. The abundance and the large variety of vaccines created not only an unprecedented intensity of vaccine related public discourse, but also a historical moment to understand vaccine hesitancy better. Yet, the heterogeneity of hesitancy by vaccine types has been neglected in the existing literature so far. We address this problem by analysing the acceptance and the assessment of five vaccine types. We use information collected with a nationally representative survey at the end of the third wave of the COVID-19 pandemic in Hungary. During the vaccination campaign, individuals could reject the assigned vaccine to wait for a more preferred alternative that enables us to quantify revealed preferences across vaccine types. We find that hesitancy is heterogenous by vaccine types and is driven by individuals' trusted source of information. Believers of conspiracy theories are more likely to evaluate the mRNA vaccines (Pfizer and Moderna) unacceptable. Those who follow the advice of politicians are more likely to evaluate vector-based (AstraZeneca and Sputnik) or whole-virus vaccines (Sinopharm) acceptable. We argue that the greater selection of available vaccine types and the free choice of the individual are desirable conditions to increase the vaccination rate in societies.

A novel perspective suggesting high sustained energy expenditure may be net protective against cancer.

Energy expenditure (EE) is generally viewed as tumorigenic, due to production of reactive oxygen species (ROS) that can damage cells and DNA. On this basis, individuals within a species that sustain high EE should be more likely to develop cancer. Here, we argue the opposite, that high EE may be net protective effect against cancer, despite high ROS production. This is possible because individuals that sustain high EE have a greater energetic capacity (=greater energy acquisition, expenditure and ability to up-regulate output), and can therefore allocate energy to multiple cancer-fighting mechanisms with minimal energetic trade-offs. Our review finds that individuals sustaining high EE have greater antioxidant production, lower oxidative stress, greater immune function and lower cancer incidence. Our hypothesis and literature review suggest that EE may indeed be net protective against cancer, and that individual variation in energetic capacity may be a key mechanism to understand the highly individual nature of cancer risk in contemporary human populations and laboratory animals. Lay summary The process of expending energy generates reactive oxygen species that can lead to oxidative stress, cell and DNA damage, and the accumulation of this damage is thought to be a major contributor to many ageing related diseases that include cancer. Here, we challenge this view, proposing how and why high energy expenditure (EE) may actually be net protective against cancer, and provide literature support for our hypothesis. We find individuals with high sustained EE have greater energetic capacity and thus can invest more in repair to counter oxidative stress, and more in immune function, both of which reduce cancer risk. Our hypothesis provides a novel mechanism to understand the highly individual nature of cancer, why taller individuals are more at risk, why physically active individuals have lower cancer risk, and why regular exercise can reduce cancer risk.

Understanding the unexplained: The magnitude and correlates of individual differences in residual variance.

Behavioral and physiological ecologists have long been interested in explaining the causes and consequences of trait variation, with a focus on individual differences in mean values. However, the majority of phenotypic variation typically occurs within individuals, rather than among individuals (as indicated by average repeatability being less than 0.5). Recent studies have further shown that individuals can also differ in the magnitude of variation that is unexplained by individual variation or environmental factors (i.e., residual variation). The significance of residual variation, or why individuals differ, is largely unexplained, but is important from evolutionary, methodological, and statistical perspectives. Here, we broadly reviewed literature on individual variation in behavior and physiology, and located 39 datasets with sufficient repeated measures to evaluate individual differences in residual variance. We then analyzed these datasets using methods that permit direct comparisons of parameters across studies. This revealed substantial and widespread individual differences in residual variance. The magnitude of individual variation appeared larger in behavioral traits than in physiological traits, and heterogeneity was greater in more controlled situations. We discuss potential ecological and evolutionary implications of individual differences in residual variance and suggest productive future research directions.

Ecological and Evolutionary Consequences of Anticancer Adaptations.

Cellular cheating leading to cancers exists in all branches of multicellular life, favoring the evolution of adaptations to avoid or suppress malignant progression, and/or to alleviate its fitness consequences. Ecologists have until recently largely neglected the importance of cancer cells for animal ecology, presumably because they did not consider either the potential ecological or evolutionary consequences of anticancer adaptations. Here, we review the diverse ways in which the evolution of anticancer adaptations has significantly constrained several aspects of the evolutionary ecology of multicellular organisms at the cell, individual, population, species, and ecosystem levels and suggest some avenues for future research.

Can Energetic Capacity Help Explain Why Physical Activity Reduces Cancer Risk?

Increased physical activity reduces cancer risk in humans, but why this whole-organism attribute reduces cancer remains unclear. Active individuals tend to have high capacity to generate energy on a sustained basis, which in turn can permit greater immune responses crucial for fighting emerging neoplasia. Thus, we suggest energetic capacity as a potential mechanism to explain the activity-cancer link, given that humans are intrinsically (not externally) energy limited. Human and rodent studies show that individuals with high energetic capacity mount greater immune responses and have lower cancer incidence; these trends persist after controlling for actual physical activity, supporting a direct role of energetic capacity. If true, exercise efforts might best target those that increase one's energetic capacity, which may be both individual and exercise specific.

Stable Matching with Uncertain Linear Preferences.

We consider the two-sided stable matching setting in which there may be uncertainty about the agents' preferences due to limited information or communication. We consider three models of uncertainty: (1) lottery model-for each agent, there is a probability distribution over linear preferences, (2) compact indifference model-for each agent, a weak preference order is specified and each linear order compatible with the weak order is equally likely and (3) joint probability model-there is a lottery over preference profiles. For each of the models, we study the computational complexity of computing the stability probability of a given matching as well as finding a matching with the highest probability of being stable. We also examine more restricted problems such as deciding whether a certainly stable matching exists. We find a rich complexity landscape for these problems, indicating that the form uncertainty takes is significant.

TRPM2-mediated extracellular Ca2+ entry promotes acinar cell necrosis in biliary acute pancreatitis.

KEY POINTS: Acute biliary pancreatitis is a significant clinical challenge as currently no specific pharmaceutical treatment exists. Intracellular Ca2+ overload, increased reactive oxygen species (ROS) production, mitochondrial damage and intra-acinar digestive enzyme activation caused by bile acids are hallmarks of acute biliary pancreatitis. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. We demonstrated that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2 O2 treatment and contributed to bile acid-induced extracellular Ca2+ influx in acinar cells, which promoted acinar cell necrosis in vitro and in vivo. These results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis. ABSTRACT: Acute biliary pancreatitis poses a significant clinical challenge as currently no specific pharmaceutical treatment exists. Disturbed intracellular Ca2+ signalling caused by bile acids is a hallmark of the disease, which induces increased reactive oxygen species (ROS) production, mitochondrial damage, intra-acinar digestive enzyme activation and cell death. Because of this mechanism of action, prevention of toxic cellular Ca2+ overload is a promising therapeutic target. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. However, the expression and possible functions of TRPM2 in the exocrine pancreas remain unknown. Here we found that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2 O2 treatment. TRPM2 activity was found to contribute to bile acid-induced extracellular Ca2+ influx in acinar cells, but did not have the same effect in ductal cells. The generation of intracellular ROS in response to bile acids was remarkably higher in pancreatic acinar cells compared to isolated ducts, which can explain the difference between acinar and ductal cells. This activity promoted acinar cell necrosis in vitro independently from mitochondrial damage or mitochondrial fragmentation. In addition, bile-acid-induced experimental pancreatitis was less severe in TRPM2 knockout mice, whereas the lack of TRPM2 had no protective effect in cerulein-induced acute pancreatitis. Our results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis.

Automated Quantitative Relaxometry for Deep Neuromuscular Blockade in Robot-Assisted Prostatectomy.

PURPOSE: During pneumoperitoneum (PP) for robot-assisted prostatectomy, a deep neuromuscular block (NMB) is necessary. New relaxometry equipment permits maintenance of profound NMB in order to improve patient safety and surgical conditions. METHODS: Twenty adult patients undergoing robot-assisted prostatectomy were included. Under automated quantitative relaxometry with the TOFcuffTM device, rocuronium dosing was adapted with the aim to keep NMB at deep levels. The time fractions with intense block (PTC 0), adequately deep block (PTC 1 to 3) and a not sufficiently deep block (PTC > 3) were quantified. RESULTS: An optimally deep block (PTC 1-3) was achieved during 110 ± 38 min (50 ± 15%). Intense block was found during 60 ± 45 min (27 ± 18%) of total PP time. Values of PTC > 3 lasted 60 ± 45 min (23 ± 17%). Median PTC always remained between 1 and 3. Inadvertent movements during PP were never encountered, and operation conditions as reported by the surgeons were excellent. CONCLUSION: Our technique of controlled profound NMB by repetitive bolus doses achieved its goal in 77% of PP time. Under automated quantitative relaxometry, an optimized rocuronium dosing strategy should be applied to maintain a high level of safety and adequate operation conditions without risking an unnecessary prolongation of NMB into the post-pneumoperitoneum period.

Impact of retrograde transillumination while securing the airway in obese patients undergoing bariatric surgery.

Video laryngoscopy (VL) is a well-established technique used in anaesthetising obese patients who present with higher risks of airway-related difficulties and desaturations due to shorter safe apnoea periods. However, VL has certain limitations and may fail. We present the Infrared Red Intubation System (IRRIS), a new technique facilitating glottis identification in severely obese patients undergoing anaesthesia for bariatric surgery. This single-centre, prospective trial assessed the efficacy of the IRRIS for VL tracheal intubation in 20 severely obese adult patients undergoing elective bariatric surgery under general anaesthesia. We assessed the ability of the IRRIS to differentiate the transilluminated glottis from the oesophagus and laryngeal folds and evaluated the ease of intubation. The average weight in the investigated patient cohort was 145 ± 29 kg, the suprasternal tissue thickness was 12 ± 4 mm. The median IQR [range] larynx recognition time was 10 [2-50] s, which was similar to that of lean patients. The degree of obesity correlated with the duration to achieve optimal laryngoscopic view and complete the intubation procedure. We achieved successful VL insertion on the first attempt in 13 of 20 cases (65%), and on the second attempt in 7 cases (35%), emphasising the increased probability of successful intubation on the first attempt. Tracheal intubation with the IRRIS lasted 50 [IQR 20-100] s. The lowest SpO2 during intubation was 98 [IQR 83-100] %. Addition of IRRIS to VL insertion facilitated the intubation of difficult airways in severely obese patients. IRRIS improves the visualization of the intubation pathway by selectively highlighting the airway entrance and shortens the time to successfully conclude the intubation procedure.