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The active force of mammalian skeletal muscle is reduced at low temperatures. Caremani et al. reveal that this is due to the rise of a population of myosin motors captured in a refractory state insensitive to muscle activation., Myosin motors in the thick filament of resting striated (skeletal and cardiac) muscle are trapped in an OFF state, in which the motors are packed in helical tracks on the filament surface, inhibiting their interactions with actin and utilization of ATP. To investigate the structural changes induced in the thick filament of mammalian skeletal muscle by changes in temperature, we collected x-ray diffraction patterns from the fast skeletal muscle extensor digitorum longus of the mouse in the temperature range from near physiological (35°C) to 10°C, in which the maximal isometric force (T0) shows a threefold decrease. In resting muscle, x-ray reflections signaling the OFF state of the thick filament indicate that cooling produces a progressive disruption of the OFF state with motors moving away from the ordered helical tracks on the surface of the thick filament. We find that the number of myosin motors in the OFF state at 10°C is half of that at 35°C. At T0, changes in the x-ray signals that report the fraction and conformation of actin-attached motors can be explained if the threefold decrease in force associated with lowering temperature is due not only to a decrease in the force-generating transition in the actin-attached motors but also to a twofold decrease in the number of such motors. Thus, lowering the temperature reduces to the same extent the fraction of motors in the OFF state at rest and the fraction of motors attached to actin at T0, suggesting that motors that leave the OFF state accumulate in a disordered refractory state that makes them unavailable for interaction with actin upon stimulation. This regulatory effect of temperature on the thick filament of mammalian skeletal muscle could represent an energetically convenient mechanism for hibernating animals.

Myosin molecules in the relaxed thick filaments of striated muscle have a helical arrangement in which the heads of each molecule interact with each other, forming the interacting-heads motif (IHM). In relaxed mammalian skeletal muscle, this helical ordering occurs only at temperatures >20°C and is disrupted when temperature is decreased. Recent x-ray diffraction studies of live tarantula skeletal muscle have suggested that the two myosin heads of the IHM (blocked heads [BHs] and free heads [FHs]) have very different roles and dynamics during contraction. Here, we explore temperature-induced changes in the BHs and FHs in relaxed tarantula skeletal muscle. We find a change with decreasing temperature that is similar to that in mammals, while increasing temperature induces a different behavior in the heads. At 22.5°C, the BHs and FHs containing ADP.Pi are fully helically organized, but they become progressively disordered as temperature is lowered or raised. Our interpretation suggests that at low temperature, while the BHs remain ordered the FHs become disordered due to transition of the heads to a straight conformation containing Mg.ATP. Above 27.5°C, the nucleotide remains as ADP.Pi, but while BHs remain ordered, half of the FHs become progressively disordered, released semipermanently at a midway distance to the thin filaments while the remaining FHs are docked as swaying heads. We propose a thermosensing mechanism for tarantula skeletal muscle to explain these changes. Our results suggest that tarantula skeletal muscle thick filaments, in addition to having a superrelaxation–based ATP energy-saving mechanism in the range of 8.5–40°C, also exhibit energy saving at lower temperatures (

International audience; The duration of daytime light phase (photoperiod) controls reproduction in seasonal mammals. Syrian hamsters are sexually active when exposed to long photoperiod, while gonadal atrophy is observed after exposure to short photoperiod. The photorefractory period, or photorefractoriness, is a particular state of spontaneous recrudescence of sexual activity that occurs after a long-term exposure to short photoperiod. Expression of core clock genes in the master circadian clock contained in the suprachiasmatic nuclei depends on photoperiodic conditions. Interestingly, the expression of the Clock gene is also modified in photorefractory Syrian hamsters. Since melatonin and testosterone levels in seasonal species are dependent on photoperiod, photoperiodic variations of Clock mRNA levels in the suprachiasmatic clock could be a consequence of these hormonal changes. To test this hypothesis, we analysed the effects of pinealectomy on Clock mRNA changes due to long to short photoperiod transition and of gonadectomy on Clock mRNA levels in photorefractory period. Our data show that the suprachiasmatic integration of the short photoperiod (assessed by a rhythmic expression profile of Clock) is independent of the presence of melatonin. Furthermore, constitutively low expression of Clock observed during the photorefractory period does not require the presence of either melatonin or testosterone. However, we show that both hormones provide positive feedback on average levels of Clock expression. Thus, our data support the hypothesis that daily variations of Clock levels in the suprachiasmatic nuclei are influenced by photoperiodic changes and the time spent in short photoperiod, independently of seasonal modifications of melatonin or testosterone levels

OBJECTIVE Cochlear implant manufacturers utilize different artifact-reduction methods to measure electrically evoked compound action potentials (ECAPs) in the clinical software. Two commercially available artifact-reduction techniques include forward masking (FwdMsk) and alternating polarity (AltPol). AltPol assumes that responses to the opposing polarities are equal, which is likely problematic. On the other hand, FwdMsk can yield inaccurate waveforms if the masker does not effectively render all neurons into a refractory state. The goal of this study was to compare ECAP thresholds, amplitudes, and slopes of the amplitude growth functions (AGFs) using FwdMsk and AltPol to determine whether the two methods yield similar results. DESIGN ECAP AGFs were obtained from three electrode regions (basal, middle, and apical) across 24 ears in 20 Cochlear Ltd. recipients using both FwdMsk and AltPol methods. AltPol waveforms could not be resolved for recipients of devices with the older-generation chip (CI24R(CS); N = 6). RESULTS Results comparing FwdMsk and AltPol in the CI24RE- and CI512-generation devices showed significant differences in threshold, AGF slope, and amplitude between methods. FwdMsk resulted in lower visual-detection thresholds (p < 0.001), shallower slopes (p = 0.004), and larger amplitudes (p = 0.03) compared with AltPol. CONCLUSIONS Results from this study are consistent with recent findings showing differences in ECAP amplitude and latency between polarities for human CI recipients. When averaged, these differences likely result in a reduced ECAP response with AltPol. The next step will be to separate the effects of artifact-reduction method and stimulus polarity to determine the relative effects of each.

Diffuse Large B Cell Lymphoma (DLBCL) is a frequent subtype of B-cell lymphoma [1]. The overall survival rate in DLBCL patients has been increasing since the addition of Rituximab to the chemothera...

Memory is mainly understood as the recollection of past events. The human brain and its simplest unit, the synapse, belong to the places in which such memories are physically stored. From an experimental point of view, memory can be tested in humans by recall. However, in other organisms, memory is reflected in its use by individuals to learn about and adapt their behavior to their environment. Under this criterion, even unicellular organisms are able to learn from their environments and show the ability to adapt their responses to repeating stimuli. This indicates that they are able to keep track of their histories and use these traces to elaborate adapted responses, making these traces akin to memory encodings. Understanding these phenomena may even help us to dissect part of the rather complex molecular orchestration happening in our synapses. When exposed unsuccessfully to mating pheromone, i.e. when mating does not happen, budding yeast cells become refractory to the mating signal. This refractory state is restricted to the mother cell and not inherited by the daughter cells, even though it is stable for most if not the entire life span of the mother cell. Interestingly, both stability and asymmetric segregation of the acquired state are explained by the molecular mechanism underlying its establishment, which shows important analogies and distinctions to prions. Here we discuss these similarities and differences.

Several aspects of chronologic and biologic aging in the human choroid are reviewed from the literature. They often reveal methodological problems for age-dependent changes of the following parameters: choroidal thickness, choroidal pigmentation, choroidal vasculature and blood flow, and choroidal innervation. On reinterpreting some data of studies concerning Bruch’s membrane, changes observed at different age points seem more likely to be nonlinear. Concluding from the data presented so far, chronologic aging should not be used as a factor for physiological changes in the human choroid. Longitudinal study designs are necessary to further establish the impact of age. Meanwhile, a more biologic oriented model of aging processes in the choroid should be established, including specified conditions (e.g., light exposure and refractory state). This would help to define more individual strategies for prevention and early stages of a certain defined disease.

Endotoxin tolerance is a phenomenon where exposure of innate immune cells to lipopolysaccharide (LPS) induces a refractory state to subsequent endotoxin exposures, which is characterized by a lack ...

We show cellular automata (CA) configurations obtained in our studies of spacetime dynamics on aperiodic tilings and reversible self-reproducing CA. The families of CA considered have almost nothing in common but their unconventionality. In 2012 Goucher found a glider propagating CA on Penrose tilings [75]. His work was inspired by the study of the variants of the Game of Life on Penrose tilings conducted by Owens and Stepney [130, 131].

To characterize information propagation on online microblogs, we propose a diffusion model (SCIR) which contains four possible states: Susceptible, contacted, infected and refractory. Agents that read the information but have not decided to spread it, stay in the contacted state. They may become infected or refractory, and both the infected and refractory state are stable. Results show during the evolution process, more contacted agents appear in scale-free networks than in regular lattices. The degree based density of infected agents increases with the degree monotonously, but larger average network degree doesnʼt always mean less relaxation time.

Endotoxin (lipopolysaccharide) tolerance is characterized by a transient refractory state to a subsequent lipopolysaccharide challenge. Following human endotoxemia, ex vivo tolerance of circulating leukocytes to lipopolysaccharide resolves within 24 hrs. However, the duration of in vivo tolerance, assumed to be primarily mediated by tissue-resident macrophages, is unknown. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Clinical experimental study in 16 healthy male volunteers at an intensive care research unit. To compare ex vivo and in vivo tolerance kinetics, whole blood from healthy volunteers was stimulated with lipopolysaccharide before, 4 hrs after, and 1, 2, 3, and 4 wks following in vivo endotoxin (2 ng/kg; lipopolysaccharide derived from Escherichia coli O:113) administration. Furthermore, we compared the inflammatory response during two subsequent endotoxemia experiments in healthy volunteers with an interval of 2 wks. The cytokines tumor necrosis factor-α, interleukin-6, interleukin-10, interleukin-1 receptor antagonist, and transforming growth factor-β were measured.Four hours after in vivo lipopolysaccharide administration, production of tumor necrosis factor-α, interleukin-6, and interleukin-10, but not interleukin-1 receptor antagonist in ex vivo lipopolysaccharide-stimulated whole blood was diminished. Ex vivo lipopolysaccharide tolerance completely resolved within 1 week. In contrast, in vivo lipopolysaccharide tolerance was still apparent after 2 wks. Compared to the first lipopolysaccharide administration, plasma peak levels of tumor necrosis factor-α, interleukin-6, interleukin-10, interleukin-1 receptor antagonist, and transforming growth factor-β were attenuated by 46%, 36%, 45%, 10%, and 14%, respectively (all p.05).While ex vivo lipopolysaccharide tolerance quickly resolves, in vivo lipopolysaccharide tolerance persists for at least 2 wks. These findings strengthen the notion that the in vivo response to lipopolysaccharide is mediated by tissue-resident macrophages and that ex vivo stimulation does not accurately reflect the in vivo innate immune response. Intervention studies utilizing the human endotoxemia model should be performed using parallel groups rather than a crossover design.

Aim Our center evaluates approximately 100 platelet refractory patients each year. Previously, we have correlated single antigen bead MFI with platelet crossmatch results in an effort to optimize our process for selection of HLA-compatible platelets. However, we continue to struggle to appreciate when antibodies to human platelet antigens (HPA) are also contributing to the platelet refractory state. In this study, our aim is to understand the relationship between HPA antibody testing (PakPlus, Immucor) and platelet crossmatch (CaptureP, Immucor). Methods One patient sample with a singular & strong specificity, HPA-1a, was identified based on PakPlus testing. This sample was also negative for HLA antibodies based on PakPlus testing. The plasma was then diluted and the PakPlus result, optical density (OD), was determined at each dilution. Ten antigen-positive platelet units were crossmatched with the battery of plasma dilutions. The strength of the platelet crossmatch was graded by one technologist, blinded to the dilution, with 4+ being strong positive to negative. Results The patient sample demonstrated a fairly linear dilution of HPA-1a, beginning with a neat result of OD 1.33. All 10 antigen-positive platelet units were positive at OD 0.42 or greater, yet negative at OD 0.04. There was platelet-specific variability between OD 0.3 and OD 0.06 (see Table 1). Conclusions These results demonstrate that HPA antibodies cause crossmatch positivity at low OD. The variability seen may be due to homozygosity versus heterozygosity of antigen expression. These initial results suggest that a PakPlus result as low as OD 0.06 may cause incompatibility in the platelet crossmatch and could be considered when selecting platelets for the platelet refractory patient. Download : Download high-res image (413KB) Download : Download full-size image

ADP-induced aggregation was determined at various times of incubation with ADP in unstirred human platelet rich plasma (PRP) to which adenosine deaminase was added. In the early stages of incubation the shape change response was absent, the aggregation response was poor, and not reversible. These three parameters returned slowly towards normal as the incubation proceeded. Pronounced impairment of the aggregation response was present after all added ADP had been degraded in plasma. Log dose-response (rate of aggregation) curves for the platelets incubated with ADP had shifted to higher ADP concentrations and had also a small decrease in maximal height and in the slope compared to those obtained with control platelets. However, the shift in log dose response to higher ADP concentrations was far more striking, so the increase in log dose (R) necessary to obtain the same rate of aggregation as with control PRP was taken as a measure of refractoriness of aggregation towards ADP. R increased with the time of incubation to an optimal value and then decreased. The magnitude of the optimal value and the time at which optimum was reached increased with the concentration of the ADP incubated with the platelets. The variations in R during incubation did not correlate with the breakdown of added ADP. The platelets began to recover their ability to aggregate with ADP while there was still ADP in the system.

In a two-dimensional cellular automaton model of retained excitation every excited cell stays excited if the number of excited neighbors belong to some interval, the cell takes refractory state otherwise. Every resting cell is excited if the number of excited cells in its neighborhood belong to some other interval; cell-state transition from refractory to resting state is unconditional. We classify 1296 rules of retained excitation based on how dynamics of excitable lattices develop after initial stimulation. Several modes of space-time activity dynamics are discovered: not growing but persistent domains of activity, domains with rectangular, octagonal and almost circular growth, amoeba-like growing patterns, mobile and still localizations.

The presence in the brain of closed neural structures has long been observed (Lorento de No in J Neurophysiol 1:207–244, 1938; Eccles in The physiology of synapses. Mir, Moscow, (1966); Rosenblatt in Principles of neurodynamics, Mir, Moscow, 1965), and this points to the importance of the role that closed neural structures may play in ring neural formation in mechanisms of memory.

This chapter addresses the development of novel countermeasures against nerve agent poisoning to improve existing prophylactic and post-exposure treatments. Effective prophylactic therapies may be difficult to achieve without causing undesirable side effects. Hence, it appears pertinent to reduce reliance on medical pre-treatment. However, the task to develop treatments with efficacy well after exposure to nerve agents represents a great challenge because of the refractory state of seizure activity in the victims. Medical therapies created through studies of microinfusion of anticonvulsants into seizure-controlling sites in the forebrain of rats seem to have promising properties. It is crucial that anticonvulsant drugs do not decrease the action of the respiratory center in the brainstem of poisoned victims. The ultimate aim should be to find well-tolerated anticonvulsants that can be used by military and civilian personnel, regardless of the time after nerve agent intoxication.

International audience; The Network Noisy Leaky Integrate and Fire equation is among the simplest model allowing for a self-consistent description of neural networks and gives a rule to determine the probability to find a neuron at the potential $v$. However, its mathematical structure is still poorly understood and, concerning its solutions, very few results are available. In the midst of them, a recent result shows blow-up in finite time for fully excitatory networks. The intuitive explanation is that each firing neuron induces a discharge of the others; thus increases the activity and consequently the discharge rate of the full network. In order to better understand the details of the phenomena and show that the equation is more complex and fruitful than expected, we analyze further the model. We extend the finite time bow-up result to the case when neurons, after firing, enter a refractory state for a given period of time. We also show that spontaneous activity may occur when, additionally, randomness is included on the firing potential $V_F$ in regimes where blow-up occurs for a fixed value of $V_F$.

Cellular automata is a universal tool in literally any field of sciences and engineering yet more applications and weird discoveries are to come. We show how three barely related natural phenomena — conductivity of an excitable medium, networks of resistors with memory and structure of schizotypy versus cognitive control mental space -— are represented in two-dimensional cellular automata with two or three states, and what discoveries we made using these models. This is an abstract of the talk at the conference on cellular automata, thus we do not provide any basics on cellular automata.

Endotoxin tolerance was first described in a study that exposed animals to a sublethal dose of bacterial endotoxin. The animals subsequently survived a lethal injection of endotoxin. This refractory state is associated with the innate immune system and, in particular, with monocytes and macrophages, which act as the main participants. Several mechanisms are involved in the control of endotoxin tolerance; however, a full understanding of this phenomenon remains elusive. A number of recent reports indicate that clinical examples of endotoxin tolerance include not only sepsis but also diseases such as cystic fibrosis and acute coronary syndrome. In these pathologies, the risk of new infections correlates with a refractory state. This review integrates the molecular basis and clinical implications of endotoxin tolerance in various pathologies.