•An electrically coupled pacemaker network in electric fish sets the timing for its high-frequency electric organ discharge.•Synaptic inputs modulate the timing of this pacemaker on millisecond ...timescales to produce electrocommunication signals.•These synaptic inputs cause variable resetting of pacemaker neurons resulting in transient desynchronization at the network level.•Computational models illustrate how network connectivity can influence the temporal features of pacemaker resetting.•Differences in pacemaker network connectivity may underlie diversity in communication signals across species.
Neuronal networks can produce stable oscillations and synchrony that are under tight control yet flexible enough to rapidly switch between dynamical states. The pacemaker nucleus in the weakly electric fish comprises a network of electrically coupled neurons that fire synchronously at high frequency. This activity sets the timing for an oscillating electric organ discharge with the lowest cycle-to-cycle variability of all known biological oscillators. Despite this high temporal precision, pacemaker activity is behaviorally modulated on millisecond time-scales for the generation of electrocommunication signals. The network mechanisms that allow for this combination of stability and flexibility are not well understood. In this study, we use an in vitro pacemaker preparation from Apteronotus leptorhynchus to characterize the neural responses elicited by the synaptic inputs underlying electrocommunication. These responses involve a variable increase in firing frequency and a prominent desynchronization of neurons that recovers within 5 oscillation cycles. Using a previously developed computational model of the pacemaker network, we show that the frequency changes and rapid resynchronization observed experimentally are most easily explained when model neurons are interconnected more densely and with higher coupling strengths than suggested by published data. We suggest that the pacemaker network achieves both stability and flexibility by balancing coupling strength with interconnectivity and that variation in these network features may provide a substrate for species-specific evolution of electrocommunication signals.
Assessment of personality disorders (PD) has been hindered by reliance on the problematic categorical model embodied in the most recent Diagnostic and Statistical Model of Mental Disorders (DSM), ...lack of consensus among alternative dimensional models, and inefficient measurement methods. This article describes the rationale for and early results from a multiyear study funded by the National Institute of Mental Health that was designed to develop an integrative and comprehensive model and efficient measure of PD trait dimensions. To accomplish these goals, we are in the midst of a 5-phase project to develop and validate the model and measure. The results of Phase 1 of the project-which was focused on developing the PD traits to be assessed and the initial item pool-resulted in a candidate list of 59 PD traits and an initial item pool of 2,589 items. Data collection and structural analyses in community and patient samples will inform the ultimate structure of the measure, and computerized adaptive testing will permit efficient measurement of the resultant traits. The resultant Computerized Adaptive Test of Personality Disorder (CAT-PD) will be well positioned as a measure of the proposed DSM-5 PD traits. Implications for both applied and basic personality research are discussed.
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Dostopno za:
BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Oxidative damage is one of the hallmarks of the aging process. The current study evaluated effects of two proprietary antioxidant-based ingredients, rosemary extract and spearmint extract ...containing carnosic acid and rosmarinic acid, respectively, on learning and memory in the SAMP8 mouse model of accelerated aging. The two rosemary extracts contained carnosic acid (60% or 10% carnosic acid) and one spearmint extract contained 5% rosmarinic acid. Three doses of actives in each extract were tested: 32, 16, 1.6 or 0 mg/kg. After 90 days of treatment mice were tested in T-maze foot shock avoidance, object recognition and lever press. Rosemary extract containing 60% carnosic acid improved acquisition and retention in T-maze foot shock, object recognition and lever press. Rosemary extract with 10% carnosic acid improved retention in T-maze foot shock avoidance and lever press. Spearmint with 5% rosmarinic acid improved acquisition and retention in T-maze foot shock avoidance and object recognition. 4-hydroxynonenal (HNE) was reduced in the brain cortex after treatment with all three extracts (P < 0.001) compared to the vehicle treated SAMP8. Protein carbonyls were reduced in the hippocampus after administration of rosemary with 10% carnosic acid (P < 0.05) and spearmint containing 5% rosmarinic acid (P < 0.001). The current results indicate that the extracts from spearmint and rosemary have beneficial effects on learning and memory and brain tissue markers of oxidation that occur with age in SAMP8 mice.
Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. ...GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.
Pregnancy is a common immunization event, but the molecular mechanisms and immunological consequences provoked by pregnancy remain largely unknown. We used mouse models and human transplant registry ...data to reveal that pregnancy induced exhausted CD8 T cells (Preg-TEX), which associated with prolonged allograft survival. Maternal CD8 T cells shared features of exhaustion with CD8 T cells from cancer and chronic infection, including transcriptional down-regulation of ribosomal proteins and up-regulation of TOX and inhibitory receptors. Similar to other models of T cell exhaustion, NFAT-dependent elements of the exhaustion program were induced by fetal antigen in pregnancy, whereas NFAT-independent elements did not require fetal antigen. Despite using conserved molecular circuitry, Preg-TEX cells differed from TEX cells in chronic viral infection with respect to magnitude and dependency of T cell hypofunction on NFAT-independent signals. Altogether, these data reveal the molecular mechanisms and clinical consequences of maternal CD8 T cell hypofunction and identify pregnancy as a previously unappreciated context in which T cell exhaustion may occur.
Motion parallax in electric sensing Pedraja, Federico; Hofmann, Volker; Lucas, Kathleen M. ...
Proceedings of the National Academy of Sciences - PNAS,
01/2018, Letnik:
115, Številka:
3
Journal Article
Recenzirano
Odprti dostop
A crucial step in forming spatial representations of the environment involves the estimation of relative distance. Active sampling through specific movements is considered essential for optimizing ...the sensory flow that enables the extraction of distance cues. However, in electric sensing, direct evidence for the generation and exploitation of sensory flow is lacking. Weakly electric fish rely on a self-generated electric field to navigate and capture prey in the dark. This electric sense provides a blurred representation of the environment, making the exquisite sensory abilities of electric fish enigmatic. Stereotyped back-and-forth swimming patterns reminiscent of visual peering movements are suggestive of the active generation of sensory flow, but how motion contributes to the disambiguation of the electrosensory world remains unclear. Here, we show that a dipole-like electric field geometry coupled to motion provides the physical basis for a nonvisual parallax. We then show in a behavioral assay that this cue is used for electrosensory distance perception across phylogenetically distant taxa of weakly electric fish. Notably, these species electrically sample the environment in temporally distinct ways (using discrete pulses or quasisinusoidal waves), suggesting a ubiquitous role for parallax in electric sensing. Our results demonstrate that electrosensory information is extracted from sensory flow and used in a behaviorally relevant context. A better understanding of motion-based electric sensing will provide insight into the sensorimotor coordination required for active sensing in general and may lead to improved electric field-based imaging applications in a variety of contexts.
The dispersal of early humans from Africa by 1.75 Myr ago led to a marked expansion of their range, from the island of Flores in the east to the Iberian peninsula in the west. This range encompassed ...tropical forest, savannah and Mediterranean habitats, but has hitherto not been demonstrated beyond 45° N. Until recently, early colonization in Europe was thought to be confined to the area south of the Pyrenees and Alps. However, evidence from Pakefield (Suffolk, UK) at ∼0.7 Myr indicated that humans occupied northern European latitudes when a Mediterranean-type climate prevailed. This provided the basis for an ‘ebb and flow’ model, where human populations were thought to survive in southern refugia during cold stages, only expanding northwards during fully temperate climates. Here we present new evidence from Happisburgh (Norfolk, UK) demonstrating that Early Pleistocene hominins were present in northern Europe >0.78 Myr ago when they were able to survive at the southern edge of the boreal zone. This has significant implications for our understanding of early human behaviour, adaptation and survival, as well as the tempo and mode of colonization after their first dispersal out of Africa.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
To assess the addition of linagliptin as an alternative to insulin uptitration in older people with type 2 diabetes on stable insulin therapy.
Materials and Methods
This phase 4, randomized, ...multicentre, double‐blinded, placebo‐controlled, 24‐week study recruited individuals on stable insulin, with baseline HbA1c 7.0%‐10.0%, aged ≥60 years and body mass index ≤45 kg/m2. HbA1c and fasting plasma glucose were measured at study visits, and participants assessed glycaemic control with a self‐monitoring blood glucose device. Adverse events (AEs) were reported during the study.
Results
Three hundred and two participants were randomized 1:1 to linagliptin 5 mg qd and placebo, with one third of patients from Japan. Study population age and HbA1c (baseline mean ± SD) were 72.4 ± 5.4 years and 8.2 ± 0.8%, respectively; ~80% of participants were aged ≥70 years; 80% had macrovascular complications, one third had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2; and half had been diagnosed with diabetes for >15 years. Linagliptin significantly improved glucose control at 24 weeks (HbA1c‐adjusted mean change vs. placebo: –0.63%; P <0.0001) and the probability of achieving predefined HbA1c targets without hypoglycaemia (HbA1c <8.0%: OR 2.02; P <0.05 and HbA1c <7.0%: OR 2.44; P <0.01). Linagliptin versus placebo was well tolerated, with similar incidences of AEs, including clinically important hypoglycaemia (blood glucose <54 mg/dL) or severe hypoglycaemia.
Conclusions
Addition of linagliptin improves glucose control without an excess of hypoglycaemia in older patients with type 2 diabetes on stable insulin therapy.
The transmembrane ionic currents that underlie changes in a cell’s membrane potential give rise to electric fields in the extracellular space. In the context of brain activity, these electric fields ...form the basis for extracellularly recorded signals such as multiunit activity, local field potentials and electroencephalograms. Understanding the underlying neuronal dynamics and localizing current sources using these signals is often challenging, and therefore effective computational modeling approaches are critical. Typically, the electric fields from neural activity are modeled in a post-hoc form, i.e. a traditional neuronal model is used to first generate the membrane currents, which in turn are then used to calculate the electric fields. When the conductivity of the extracellular space is high, the electric fields are weak, and therefore treating membrane currents and electric fields separately is justified. However, in brain regions of lower conductivity, extracellular fields can feed back and significantly influence the underlying transmembrane currents and dynamics of nearby neurons – this is often referred to as ephaptic coupling. The closed-loop nature of ephaptic coupling cannot be modeled using the post-hoc approaches implemented by existing software tools; instead, electric fields and neuronal dynamics must be solved simultaneously. To this end, we have developed a generalized modeling toolbox for studying ephaptic coupling in compartmental neuron models: ELFENN (ELectric Field Effects in Neural Networks). In open loop conditions, we validate the separate components of ELFENN for modeling membrane dynamics and associated field potentials against standard approaches (NEURON and LFPy). Unlike standard approaches however, ELFENN enables the closed-loop condition to be modeled as well, in that the field potentials can feed back and influence membrane dynamics. As an example closed-loop case, we use ELFENN to study phase-locking of action potentials generated by a population of axons running parallel in a bundle. Being able to efficiently explore ephaptic coupling from a computational perspective using tools such as ELFENN will allow us to better understand the physical basis of electric fields in the brain, as well as the conditions in which these fields may influence neuronal dynamics in general.
Regulating membrane potential and synaptic function contributes significantly to the energetic costs of brain signaling, but the relative costs of action potentials (APs) and synaptic transmission ...during high-frequency firing are unknown. The continuous high-frequency (200-600Hz) electric organ discharge (EOD) of Eigenmannia, a weakly electric fish, underlies its electrosensing and communication. EODs reflect APs fired by the muscle-derived electrocytes of the electric organ (EO). Cholinergic synapses at the excitable posterior membranes of the elongated electrocytes control AP frequency. Based on whole-fish O2 consumption, ATP demand per EOD-linked AP increases exponentially with AP frequency. Continual EOD-AP generation implies first, that ion homeostatic processes reliably counteract any dissipation of posterior membrane ENa and EK and second that high frequency synaptic activation is reliably supported. Both of these processes require energy. To facilitate an exploration of the expected energy demands of each, we modify a previous excitability model and include synaptic currents able to drive APs at frequencies as high as 600 Hz. Synaptic stimuli are modeled as pulsatile cation conductance changes, with or without a small (sustained) background conductance. Over the full species range of EOD frequencies (200-600 Hz) we calculate frequency-dependent "Na+-entry budgets" for an electrocyte AP as a surrogate for required 3Na+/2K+-ATPase activity. We find that the cost per AP of maintaining constant-amplitude APs increases nonlinearly with frequency, whereas the cost per AP for synaptic input current is essentially constant. This predicts that Na+ channel density should correlate positively with EOD frequency, whereas AChR density should be the same across fish. Importantly, calculated costs (inferred from Na+-entry through Nav and ACh channels) for electrocyte APs as frequencies rise are much less than expected from published whole-fish EOD-linked O2 consumption. For APs at increasingly high frequencies, we suggest that EOD-related costs external to electrocytes (including packaging of synaptic transmitter) substantially exceed the direct cost of electrocyte ion homeostasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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