Gaze stabilization reflexes in the mouse: New tools to study vision and sensorimotor

__abstract__ Gaze stabilization reflexes are a popular model system in neuroscience for connecting neurophysiology and behavior as well as studying the neural correlates of behavioral plasticity. These compensatory eye movements are one of the simplest motor behaviors, consisting of a more or less spherical object that rotates with three degrees of freedom, without significantly changing the load during a movement trajectory. Additionally, it is a model system where the sensory input, consisting of visual and/or vestibular stimulation, can be fully controlled. The output, reflexive compensatory eye movements and electrophysiological activity, can be recorded and correlated with the sensory input. By manipulating those reflexive eye movements by using different combinations of sensory input, motor learning can be studied in a well‐controlled environment. In this thesis, we describe several innovative approaches that can be added to the neuroscientific arsenal. We are the first lab to describe how to record three dimensional eye movements in mice using video‐oculography. Additionally, we describe how compensatory eye movements can be used to quantify contrast sensitivity; the ability to detect small increments in shades of gray on a uniform background, which is one of the main limiting factors in a wide variety of visual tasks. This new and sensitive method is useful in characterizing mouse models where vision is affected as a result of mutations, aging, retinal degeneration or neurological impairment of the visual system

Paradigm of biased PAR1 (protease-activated receptor-1) activation and inhibition in endothelial cells dissected by phosphoproteomics

Thrombin is the key serine protease of the coagulation cascade and mediates cellular responses by activation of PARs (protease-activated receptors). The predominant thrombin receptor is PAR1, and in endothelial cells (ECs), thrombin dynamically regulates a plethora of phosphorylation events. However, it has remained unclear whether thrombin signaling is exclusively mediated through PAR1. Furthermore, mechanistic insight into activation and inhibition of PAR1-mediated EC signaling is lacking. In addition, signaling networks of biased PAR1 activation after differential cleavage of the PAR1 N terminus have remained an unresolved issue. Here, we used a quantitative phosphoproteomics approach to show that classical and peptide activation of PAR1 induce highly similar signaling, that low thrombin concentrations initiate only limited phosphoregulation, and that the PAR1 inhibitors vorapaxar and parmodulin-2 demonstrate distinct antagonistic properties. Subsequent analysis of the thrombin-regulated phosphosites in the presence of PAR1 inhibitors revealed that biased activation of PAR1 is not solely linked to a specific G-protein downstream of PAR1. In addition, we showed that only the canonical thrombin PAR1 tethered ligand induces extensive early phosphoregulation in ECs. Our study provides detailed insight in the signaling mechanisms downstream of PAR1. Our data demonstrate that thrombin-induced EC phosphoregulation is mediated exclusively through PAR1, that thrombin and thrombin-tethered ligand peptide induce similar phosphoregulation, and that only canonical PAR1 cleavage by thrombin generates a tethered ligand that potently induces early signaling. Furthermore, platelet PAR1 inhibitors directly affect EC signaling, indicating that it will be a challenge to design a PAR1 antagonist that will target only those pathways responsible for tissue pathology

Using Cox's Proportional Hazard Models to Implement Optimal Strategies: An Example from Behavioural Ecology

Simple behavioural rules, or "rules of thumb", which lead to behaviour that closely approximates an optimal strategy, have generated a lot of recent interest in the field of foraging behaviour. In this paper, we derive rules of thumb from a stochastic simulation model in which the foragers behave optimally. We use a particular biological system: the patch leaving behaviour of a parasitoid. We simulate parasitoids whose patch leaving behaviour is determined by a stochastic dynamic programming (SDP) model, while allowing parasitoids to make mistakes in their estimation of host density when arriving in a patch. We use Cox's proportional hazards models to obtain statistical rules of thumb from the simulated behaviour. This represents the first use of a proportional hazard approximation to generate rules of thumb from a complex optimal strategy

The effectiveness of individual schema therapy in older adults with borderline personality disorder:Protocol of a multiple-baseline study

BackgroundThe treatment of borderline personality disorder (BPD) has been examined extensively in adults up to the age of fifty in the past quarter of a century, but there is still a world to discover in treating BPD in older adults. The aim of the study is to investigate the effectiveness of schema therapy in older adults with BPD.Methods/designA multiple baseline design is used in which participants are randomly assigned to baseline length. The primary outcome measure is assessed weekly and consists of the credibility of negative core beliefs. Secondary outcome measures are quality of life, psychological distress, early maladaptive schemas, schema modes, severity of BPD symptoms and meeting the criteria for BPD. Ten older adults (age > 60 years) with BPD are treated with schema therapy, with weekly sessions during one year. This treatment phase is preceded by a baseline phase varying from 4 to 8 weeks. After treatment, there is a 6-month follow-up phase with monthly booster sessions.DiscussionTo our knowledge, this is the first empirical study of the effectiveness of psychotherapeutic treatment for BPD in older adults. Because of the different manifestation of BPD in later life, besides section II DSM-5 criteria, the alternative, dimensional model for personality disorders of DSM-5 is used to assess BPD in older adults

Validation of the AUDIT and AUDIT-C for hazardous drinking in community-dwelling older adults

Background: One of the best-known tools in screening for hazardous drinking is the Alcohol Use Disorders Identification Test (AUDIT) and its abbreviated form, the AUDIT-C. The aim of the present study is to determine the cut-offs of both instruments in identifying hazardous drinking in older adults. Method: A sample of 1577 older adults completed a questionnaire regarding alcohol behavior. Hazardous drinking was defined as drinking >10 units/week. Receiver operating characteristics (ROC) curves of AUDIT and AUDIT-C were calculated and cut-off scores were derived. Results: Respectively 27.3% and 12.3% of older men and women drank >10 units/week. For the AUDIT the best trade-off between sensitivity and specificity was using a cut-off of ≥5 for men and ≥4 for women, which yielded in men sensitivity and specificity values respectively of 80.7% and 81.3% and in women 100% and 71.7%, respectively. We found the AUDIT-C to perform well with an optimal cut-off of ≥5 for men and ≥4 for women, which generated in men sensitivity and specificity values respectively of 76.5% and 85.3% and in women 100% and 74.1%, respectively. Conclusion: The AUDIT-C is accurate and sufficient in screening for hazardous drinking in community-dwelling older adults if the cut-offs are tailored by gender

Возможностим развития конкуренции на рынках теплоснабжения Донбасса

Проаналізовано стан ситем теплопостачання Донбасу, виявлено зниження виробництва та відпуску теплової енергії, що викликано появою конкурента — автономного опалення. Обгрунтовано причини протиріччя законодавства, що регулює діяльність у сфері комунального теплопостачання — природної монополії, в результаті чого порушені конституційні, цивільні, споживчі права людей. Розглянуто практику регулювання ринків теплопостачання в країнах з розвиненою ринковою економікою, і можливості застосування їх досвіду в Україні. Визначено роль держави, як найважливішого регулятора, який здійснює контроль за ринком теплопостачання, і є влавником стратегічно важливих підприємств сектора. Ключові слова: централізоване теплопостачання, природна монополія, автономне опалення, конкуренція, приватний капітал, державне регулювання.Проанализировано состояние ситем теплоснабжения Донбасса, выявлено снижение производства и отпуска тепловой энергии, что вызвано появлением конкурента — автономного отопления. Обоснованы причины протеворечивости законодательства регулирующего деятельность в сфере коммунального теплоснабжения — естественной монополии, в результате чего нарушены конституционные, гражданские, потребительские права людей. Рассмотрена практика регулирования рынков теплоснабжения в странах с развитой рыночной экономикой, и возможности применения их опыта в Украине. Определена роль государства, как важнейшего регулятора, осуществляющего контроль за рынком теплоснабжения, и собственика стратегически важных предприятий сектора. Ключевые слова: централизованное теплоснабжение, естественная монополия, автономное отопление, конкуренция, частный капитал, государственное регулирование.The state of Donbass Heating System Works, showed a reduction in production and supply of heat energy that is caused by the emergence of competitors — independent heating. Substantiated reasons imperfect legislation governing activities in the field of district heating — natural monopoly, resulting in a violation of the constitutional, civil, consumer rights of people. The practical management of district heating markets in countries with developed market economies, and the possibility of applying their experience in Ukraine. Defined the place of government as an important regulator, controlling the heating market, and the owners of strategically important enterprises in the sector. Key words: district heating, natural monopoly, independent heating, competition, private capital, government regulation

Phase variable expression of capsular polysaccharide modifications allows <em>Campylobacter jejuni</em> to avoid bacteriophage infection in chickens

Bacteriophages are estimated to be the most abundant entities on earth and can be found in every niche where their bacterial hosts reside. The initial interaction between phages and Campylobacter jejuni, a common colonizer of poultry intestines and a major source of foodborne bacterial gastroenteritis in humans, is not well understood. Recently, we isolated and characterized a phage F336 resistant variant of C. jejuni NCTC11168 called 11168R. Comparisons of 11168R with the wildtype lead to the identification of a novel phage receptor, the phase variable O-methyl phosphoramidate (MeOPN) moiety of the C. jejuni capsular polysaccharide (CPS). In this study we demonstrate that the 11168R strain has gained cross-resistance to four other phages in our collection (F198, F287, F303, and F326). The reduced plaquing efficiencies suggested that MeOPN is recognized as a receptor by several phages infecting C. jejuni. To further explore the role of CPS modifications in C. jejuni phage recognition and infectivity, we tested the ability of F198, F287, F303, F326, and F336 to infect different CPS variants of NCTC11168, including defined CPS mutants. These strains were characterized by high-resolution magic angle spinning NMR spectroscopy. We found that in addition to MeOPN, the phase variable 3-O-Me and 6-O-Me groups of the NCTC11168 CPS structure may influence the plaquing efficiencies of the phages. Furthermore, co-infection of chickens with both C. jejuni NCTC11168 and phage F336 resulted in selection of resistant C. jejuni bacteria, which either lack MeOPN or gain 6-O-Me groups on their surface, demonstrating that resistance can be acquired in vivo. In summary, we have shown that phase variable CPS structures modulate phage infectivity in C. jejuni and suggest that the constant phage predation in the avian gut selects for changes in these structures leading to a continuing phage–host co-evolution