Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons.

It is now widely accepted that certain types of cognitive functions are intimately related to synchronized neuronal oscillations at both low (alpha/theta) (4-7/8-13 Hz) and high (beta/gamma) (18-35/30-70 Hz) frequencies. The thalamus is a key participant in many of these oscillations, yet the cellular mechanisms by which this participation occurs are poorly understood. Here we describe how, under appropriate conditions, thalamocortical (TC) neurons from different nuclei can exhibit a wide array of largely unrecognised intrinsic oscillatory activities at a range of cognitively-relevant frequencies. For example, both metabotropic glutamate receptor (mGluR) and muscarinic Ach receptor (mAchR) activation can cause rhythmic bursting at alpha/theta frequencies. Interestingly, key differences exist between mGluR- and mAchR-induced bursting, with the former involving extensive dendritic Ca2+ electrogenesis and being mimicked by a non-specific block of K+ channels with Ba2+, whereas the latter appears to be more reliant on proximal Na+ channels and a prominent spike afterdepolarization (ADP). This likely relates to the differential somatodendritic distribution of mGluRs and mAChRs and may have important functional consequences. We also show here that in similarity to some neocortical neurons, inhibiting large-conductance Ca2+-activated K+ channels in TC neurons can lead to fast rhythmic bursting (FRB) at approximately 40 Hz. This activity also appears to rely on a Na+ channel-dependent spike ADP and may occur in vivo during natural wakefulness. Taken together, these results show that TC neurons are considerably more flexible than generally thought and strongly endorse a role for the thalamus in promoting a range of cognitively-relevant brain rhythms

Understanding the Basis for Down Syndrome Phenotypes

Down syndrome is a collection of features that are caused by trisomy for human Chromosome 21. While elevated transcript levels of the more than 350 genes on the chromosome are primarily responsible, it is likely that multiple genetic mechanisms underlie the numerous ways in which development and function diverge in individuals with trisomy 21 compared to euploid individuals. We consider genotype–phenotype interactions with the goal of producing working concepts that will be useful for approaches to ameliorate the effects of trisomy

Vanadium Substitution Dictates H Atom Uptake at Lindqvist-type Polyoxotungstates

Understanding how modification of molecular structures changes the thermochemistry of H atom uptake can provide design criteria for the formation of highly active catalysts for reductive transformations. Herein, we describe the effect of doping an atomically precise polyoxotungstate with vanadium on proton-coupled electron transfer (PCET) reactivity. The Lindqvist-type polyoxotungstate [W6O19]2–displays reversible redox chemistry, which was found to be unchanged in the presence of acid, indicating an inability to couple reduction with protonation. However, the incorporation of a single vanadium center into the structure significantly changes the reactivity, and the potential required for one-electron reduction of [VW5O19]3– was shown to vary with the strength of the acid added. Construction of a potential-pKadiagram allowed assessment of the thermodynamics of H atom uptake, indicating BDFE(O–H) ≈ 64 kcal/mol, while chemical synthesis of the reduced/protonated derivative (TBA)3[VW5O19H] was used to probe the position of protonation. tures changes the thermochemistry of H atom uptake can providedesign criteria for the formation of highly active catalysts for reductivetransformations. Herein, we describe the effect of doping anatomically precise polyoxotungstate with vanadium on proton-coupledelectron transfer (PCET) reactivity. The Lindqvist-type polyoxotung-state [W6O19]2− displays reversible redox chemistry, which was foundto be unchanged in the presence of acid, indicating an inability tocouple reduction with protonation. However, the incorporation of asingle vanadium center into the structure significantly changes thereactivity, and the potential required for one-electron reduction of[VW5O19]3− was shown to vary with the strength of the acid added.Construction of a potential-pUnderstanding how modification of molecular struc-tures changes the thermochemistry of H atom uptake can providedesign criteria for the formation of highly active catalysts for reductivetransformations. Herein, we describe the effect of doping anatomically precise polyoxotungstate with vanadium on proton-coupledelectron transfer (PCET) reactivity. The Lindqvist-type polyoxotung-state [W6O19]2− displays reversible redox chemistry, which was foundto be unchanged in the presence of acid, indicating an inability tocouple reduction with protonation. However, the incorporation of asingle vanadium center into the structure significantly changes thereactivity, and the potential required for one-electron reduction of[VW5O19]3− was shown o vary with the strength of the acid added.Construction of a potential-pKa diagram allowed assessment of thethermodynamics of H atom uptake, indicating BDFE(O−H) ≈ 64 kcal/mol, while chemical synthesis of the reduced/protonatedderivative (TBA)3[VW5O19H] was used to probe the position of protoKa diagram allowed assessment of thethermodynamics of H atom uptake, indicating BDFE(O−H) ≈ 64 kcal/mol, while chemical synthesis of the reduced/protonatedderivative (TBA)3[VW5O19H] was used to probe the position of protonation

Enhanced tonic GABAA inhibition in typical absence epilepsy

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.peer-reviewe

Activity of cortical and thalamic neurons during the slow (<1 Hz) rhythm in the mouse in vivo

During NREM sleep and under certain types of anaesthesia, the mammalian brain exhibits a distinctive slow (<1 Hz) rhythm. At the cellular level, this rhythm correlates with so-called UP and DOWN membrane potential states. In the neocortex, these UP and DOWN states correspond to periods of intense network activity and widespread neuronal silence, respectively, whereas in thalamocortical (TC) neurons, UP/DOWN states take on a more stereotypical oscillatory form, with UP states commencing with a low-threshold Ca2+ potential (LTCP). Whilst these properties are now well recognised for neurons in cats and rats, whether or not they are also shared by neurons in the mouse is not fully known. To address this issue, we obtained intracellular recordings from neocortical and TC neurons during the slow (<1 Hz) rhythm in anaesthetised mice. We show that UP/DOWN states in this species are broadly similar to those observed in cats and rats, with UP states in neocortical neurons being characterised by a combination of action potential output and intense synaptic activity, whereas UP states in TC neurons always commence with an LTCP. In some neocortical and TC neurons, we observed ‘spikelets’ during UP states, supporting the possible presence of electrical coupling. Lastly, we show that, upon tonic depolarisation, UP/DOWN states in TC neurons are replaced by rhythmic high-threshold bursting at ~5 Hz, as predicted by in vitro studies. Thus, UP/DOWN state generation appears to be an elemental and conserved process in mammals that underlies the slow (<1 Hz) rhythm in several species, including humans

Reversible and Noisy Progression towards a Commitment Point Enables Adaptable and Reliable Cellular Decision-Making

Cells must make reliable decisions under fluctuating extracellular conditions, but also be flexible enough to adapt to such changes. How cells reconcile these seemingly contradictory requirements through the dynamics of cellular decision-making is poorly understood. To study this issue we quantitatively measured gene expression and protein localization in single cells of the model organism Bacillus subtilis during the progression to spore formation. We found that sporulation proceeded through noisy and reversible steps towards an irreversible, all-or-none commitment point. Specifically, we observed cell-autonomous and spontaneous bursts of gene expression and transient protein localization events during sporulation. Based on these measurements we developed mathematical population models to investigate how the degree of reversibility affects cellular decision-making. In particular, we evaluated the effect of reversibility on the 1) reliability in the progression to sporulation, and 2) adaptability under changing extracellular stress conditions. Results show that reversible progression allows cells to remain responsive to long-term environmental fluctuations. In contrast, the irreversible commitment point supports reliable execution of cell fate choice that is robust against short-term reductions in stress. This combination of opposite dynamic behaviors (reversible and irreversible) thus maximizes both adaptable and reliable decision-making over a broad range of changes in environmental conditions. These results suggest that decision-making systems might employ a general hybrid strategy to cope with unpredictably fluctuating environmental conditions

What are the roles involved in establishing and maintaining informational continuity of care withinfamily practice? A systematic review

Abstract Background Central to establishing continuity of care is the development of a relationship between doctor and patient/caregiver. Transfer of information between these parties facilitates the development of continuity in general; and specifically informational continuity of care. We conducted a systematic review of published literature to gain a better understanding of the roles that different parties – specifically doctors, patients, family caregivers, and technology – play in establishing and maintaining informational continuity of care within family practice. Methods Relevant published articles were sought from five databases. Accepted articles were reviewed and appraised in a consistent way. Fifty-six articles were retained following title and abstract reviews. Of these, 28 were accepted for this review. Results No articles focused explicitly on the roles involved in establishing or maintaining informational continuity of care within family practice. Most informational continuity of care literature focused on the transfer of information between settings and not at the first point of contact. Numerous roles were, however, were interpreted using the data extracted from reviewed articles. Doctors are responsible for record keeping, knowing patients' histories, recalling accumulated knowledge, and maintaining confidentiality. Patients are responsible for disclosing personal and health details, transferring information to other practitioners (including new family doctors), and establishing trust. Both are responsible for developing a relationship of trust. Technology is an important tool of informational continuity of care through holding important information, providing search functions, and providing a space for recorded information. There is a significant gap in our knowledge about the roles that family caregivers play. Conclusion The number of roles identified and the interrelationships between them indicates that establishing and maintaining informational continuity of care within family practice is a complex and multifaceted process. This synthesis of roles provided serves as an important resource for continuity of care researchers in general, for the development of continuity of care quality indicators, and for the practice of family medicine.</p

Meta-analysis of the effects of predation on animal prey abundance: evidence from UK vertebrates

Background: Controlling vertebrate predators is one of the most widespread forms of wildlife management and it continues to cause conflict between stakeholders worldwide. It is important for managers and policy-makers to make decisions on this issue that are based on the best available scientific evidence. Therefore, it is first important to understand if there is indeed an impact of vertebrate predators on prey, and then to quantify this impact. Methodology/Principal Findings: Using the UK as a case study, we use a meta-analytical approach to review the available evidence to assess the effect of vertebrate predation on animal prey abundance. We find a significant effect of predators on prey abundance across our studies. On average, there is a 1.6 fold increase in prey abundance in the absence of predation. However, we show significant heterogeneity in effect sizes, and discuss how the method of predator control, whether the predator is native or non-native, and aspects of study design, may be potential causes. Conclusions/Significance: Our results allow some cautious policy recommendations to be made regarding the management of predator and prey populations. Meta-analysis is an important tool for understanding general patterns in the effect of predators on prey abundance across studies. Such an approach is especially valuable where management decisions need to be made in the absence of site-specific information

Rheumatoid constrictive pericarditis

A 73-yr-old woman with a 4 yr history of rheumatoid arthritis presented with the clinical features of congestive cardiac failure. She had a good early response to standard therapy although she subsequently developed recurrent biventricular failure. The preservation of good ventricular function on echocardiography in the face of clinical evidence of myocardial insufficiency raised the possibility of constrictive pericarditis, which was confirmed on cardiac catheterization. Constrictive pericarditis should be considered in patients with rheumatoid arthritis who develop unexplained cardiac failure. Early diagnosis requires a high index of suspicion and cardiac catheterization may be necessary to confirm the diagnosis. Medical treatment is largely ineffective and pericardiectomy should be considered

Rheumatoid constrictive pericarditis.

A 73-yr-old woman with a 4 yr history of rheumatoid arthritis presented with the clinical features of congestive cardiac failure. She had a good early response to standard therapy although she subsequently developed recurrent biventricular failure. The preservation of good ventricular function on echocardiography in the face of clinical evidence of myocardial insufficiency raised the possibility of constrictive pericarditis, which was confirmed on cardiac catheterization. Constrictive pericarditis should be considered in patients with rheumatoid arthritis who develop unexplained cardiac failure. Early diagnosis requires a high index of suspicion and cardiac catheterization may be necessary to confirm the diagnosis. Medical treatment is largely ineffective and pericardiectomy should be considered