Based on remarks by Mr Luiz Awazu Pereira da Silva, Deputy General Manager of the BIS, with Jon Frost and Leonardo Gambacorta at the Santander International Banking Conference on "Banking on trust: Building confidence in the future", Madrid, 5 November 2019.

The cerebellum influences motor control through Purkinje target neurons, which transmit cerebellar output. Such output is required, for instance, for larval zebrafish to learn conditioned fictive swimming. The output cells, called eurydendroid neurons (ENs) in teleost fish, are inhibited by Purkinje cells and excited by parallel fibers. Here, we investigated the electrophysiological properties of glutamatergic ENs labeled by the transcription factor olig2. Action potential firing and synaptic responses were recorded in current clamp and voltage clamp from olig2⁺ neurons in immobilized larval zebrafish (before sexual differentiation) and were correlated with motor behavior by simultaneous recording of fictive swimming. In the absence of swimming, olig2⁺ ENs had basal firing rates near 8 spikes/s, and EPSCs and IPSCs were evident. Comparing Purkinje firing rates and eurydendroid IPSC rates indicated that 1-3 Purkinje cells converge onto each EN. Optogenetically suppressing Purkinje simple spikes, while preserving complex spikes, suggested that eurydendroid IPSC size depended on presynaptic spike duration rather than amplitude. During swimming, EPSC and IPSC rates increased. Total excitatory and inhibitory currents during sensory-evoked swimming were both more than double those during spontaneous swimming. During both spontaneous and sensory-evoked swimming, the total inhibitory current was more than threefold larger than the excitatory current. Firing rates of ENs nevertheless increased, suggesting that the relative timing of IPSCs and EPSCs may permit excitation to drive additional eurydendroid spikes. The data indicate that olig2⁺ cells are ENs whose activity is modulated with locomotion, suiting them to participate in sensorimotor integration associated with cerebellum-dependent learning.

SIGNIFICANCE STATEMENT The cerebellum contributes to movements through signals generated by cerebellar output neurons, called eurydendroid neurons (ENs) in fish (cerebellar nuclei in mammals). ENs receive sensory and motor signals from excitatory parallel fibers and inhibitory Purkinje cells. Here, we report electrophysiological recordings from ENs of larval zebrafish that directly illustrate how synaptic inhibition and excitation are integrated by cerebellar output neurons in association with motor behavior. The results demonstrate that inhibitory and excitatory drive both increase during fictive swimming, but inhibition greatly exceeds excitation. Firing rates nevertheless increase, providing evidence that synaptic integration promotes cerebellar output during locomotion. The data offer a basis for comparing aspects of cerebellar coding that are conserved and that diverge across vertebrates.

Maintenance of cardiorespiratory homeostasis depends on autonomic reflexes controlled by neuronal circuits of the brainstem. The neurophysiology and neuroanatomy of these reflex pathways are well understood, however, the mechanisms and functional significance of autonomic circuit modulation by glial cells remain largely unknown. In the experiments conducted in male laboratory rats we show that astrocytes of the nucleus of the solitary tract (NTS), the brain area that receives and integrates sensory information from the heart and blood vessels, respond to incoming afferent inputs with [Ca²⁺]_i elevations. Astroglial [Ca²⁺]_i responses are triggered by transmitters released by vagal afferents, glutamate acting at AMPA receptors and 5-HT acting at 5-HT_2A receptors. In conscious freely behaving animals blockade of Ca²⁺-dependent vesicular release mechanisms in NTS astrocytes by virally driven expression of a dominant-negative SNARE protein (dnSNARE) increased baroreflex sensitivity by 70% (p < 0.001). This effect of compromised astroglial function was specific to the NTS as expression of dnSNARE in astrocytes of the ventrolateral brainstem had no effect. ATP is considered the principle gliotransmitter and is released by vesicular mechanisms blocked by dnSNARE expression. Consistent with this hypothesis, in anesthetized rats, pharmacological activation of P2Y₁ purinoceptors in the NTS decreased baroreflex gain by 40% (p = 0.031), whereas blockade of P2Y₁ receptors increased baroreflex gain by 57% (p = 0.018). These results suggest that glutamate and 5-HT, released by NTS afferent terminals, trigger Ca²⁺-dependent astroglial release of ATP to modulate baroreflex sensitivity via P2Y₁ receptors. These data add to the growing body of evidence supporting an active role of astrocytes in brain information processing.

SIGNIFICANCE STATEMENT Cardiorespiratory reflexes maintain autonomic balance and ensure cardiovascular health. Impaired baroreflex may contribute to the development of cardiovascular disease and serves as a robust predictor of cardiovascular and all-cause mortality. The data obtained in this study suggest that astrocytes are integral components of the brainstem mechanisms that process afferent information and modulate baroreflex sensitivity via the release of ATP. Any condition associated with higher levels of "ambient" ATP in the NTS would be expected to decrease baroreflex gain by the mechanism described here. As ATP is the primary signaling molecule of glial cells (astrocytes, microglia), responding to metabolic stress and inflammatory stimuli, our study suggests a plausible mechanism of how the central component of the baroreflex is affected in pathological conditions.

We can adapt flexibly to environment changes and search for the most appropriate rule to a context. The orbital prefrontal cortex (PFo) has been associated with decision making, rule generation and maintenance, and more generally has been considered important for behavioral flexibility. To better understand the neural mechanisms underlying the flexible behavior, we studied the ability to generate a switching signal in monkey PFo when a strategy is changed. In the strategy task, we used a visual cue to instruct two male rhesus monkeys either to repeat their most recent choice (i.e., stay strategy) or to change it (i.e., shift strategy). To identify the strategy switching-related signal, we compared nonswitch and switch trials, which cued the same or a different strategy from the previous trial, respectively. We found that the switching-related signal emerged during the cue presentation and it was combined with the strategy signal in a subpopulation of cells. Moreover, the error analysis showed that the activity of the switch-related cells reflected whether the monkeys erroneously switched or not the strategy, rather than what was required for that trial. The function of the switching signal could be to prompt the use of different strategies when older strategies are no longer appropriate, conferring the ability to adapt flexibly to environmental changes. In our task, the switching signal might contribute to the implementation of the strategy cued, overcoming potential interference effects from the strategy previously cued. Our results support the idea that ascribes to PFo an important role for behavioral flexibility.

SIGNIFICANCE STATEMENT We can flexibly adapt our behavior to a changing environment. One of the prefrontal areas traditionally associated with the ability to adapt to new contingencies is the orbital prefrontal cortex (PFo). We analyzed the switching related activity using a strategy task in which two rhesus monkeys were instructed by a visual cue either to repeat or change their most recent choice, respectively using a stay or a shift strategy. We found that PFo neurons were modulated by the strategy switching signal, pointing to the importance of PFo in behavioral flexibility by generating control over the switching of strategies.

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [¹¹C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[¹¹C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.

SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[¹¹C]ABP688 and [¹¹C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.

Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Last, we use cortical cultures derived from Dcx KO mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.

SIGNIFICANCE STATEMENT Nestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.

Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1–4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Na_v1.6 and K_v7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (~2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate.

SIGNIFICANCE STATEMENT Persistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate.

Eradicating world hunger can only be achieved if food is safe, nutritious and of good quality. Eating unsafe food increases the chances of contracting diseases and can be, in some cases, deadly. Unsafe food can also lead to rejections causing food to be wasted, which then impacts on food security. One thing is certain: there can be no food security [...]

Youth around the world are increasingly turning away from agriculture. Traditionally requiring tough manual labour and offering low wages, agriculture does not often appeal to new generations who generally prefer to try their luck finding jobs in cities.  

A recent excavation located the first physical evidence of the capital of the Maya kingdom of Sak Tz'i', founded in 750 B.C.

Precious data points logged on paper are in dire need of a hero. Could it be you?

Architects and designers restored royal ruins across Europe to their former glory

New research indicates that Iron Age Britons venerated brown hares and chickens long before modern Easter celebrations

New scans suggest unhatched dinosaurs reabsorbed a set of teeth during development

The sites include the 5,000-year-old tomb of Meresankh III, the Red Monastery and the Mosque-Madrassa of Sultan Barquq

The Rubin Museum of Art and the Smithsonian's National Museum of Asian Art offer an array of relaxing experiences

The solitary species is hard to spot on camera, and they're the only canine that lives in the Amazon rainforest

Modified hospital designs have become necessary as the first wave of the pandemic tears through U.S. communities

Find the capital cities, working from a list of state names

vitality

A sled in the Smithsonian collections marks the historic race

Hadrian’s Wall was a 73 mile barrier stretching from coast to coast, splitting the warlike north of Britain from the more docile south. It was the Roman Empire’s way of imposing peace in a hostile land

Veteran musher Lance Mackey has had his 21st place finish in this year's Iditarod Trail Sled Dog Race vacated because of a failed drug test, race officials announced Thursday.

The tourism and hospitality industries, which play a large role in the economy of almost every community in northwestern Ontario, are taking a beating during the COVID-19 pandemic. Now, the manager of Tourism Thunder Bay is figuring out how “dire” the situation is, and what could be done to help.

Provincial Police have a suspect in custody after a firearms incident Thursday morning at the hospital in the small northwestern Ontario community of Rainy River.

Parents-to-be who will have their new child delivered at the Thunder Bay Regional Health Sciences Centre have to follow a different set of guidelines than found at many other hospitals across Ontario.

Este año en el mes en que se llevó a cabo el mantenimiento anual de Logos Hope en Uruguay, la tripulante Cecilia* de Argentina se unió a un pequeño equipo que sirve en Asia Central. Mientras estuvo allí, pudo asistir a dos iglesias subterráneas que desbordaban de esperanza y fe.

The only way to solubilize many antigens for immunoprecipitation is by denaturation. This cell lysis protocol is ideally suited for this purpose to release proteins from complex structures or reveal antibody epitopes hidden within native proteins. Short linear epitopes may not be accessible to antibodies within the native tertiary and quaternary protein structures, but they become exposed upon the unraveling of proteins, exposing their secondary structure. Antibodies otherwise not suitable for the immunoprecipitation of proteins prepared under nondenaturing conditions are now able to bind these antigens of interest in cell lysates prepared under denaturing conditions. These antibodies may also work well for immunoblotting purposes when the protein target is completely denatured. Harvested cells in this protocol are washed in tris-buffered saline (TBS) before lysis in 2% sodium dodecyl sulfate (SDS)-containing Lysis buffer for 10 min at 100°C. The resulting sample is diluted 20-fold in TBS to reduce the SDS concentration to ≤0.1% before the addition of an antibody for immunoprecipitation. Addition of 2% bovine serum albumin (BSA) or 0.1% Nonidet P-40 to the TBS before an immunoprecipitation, respectively, ensures either removal of SDS from the target protein or retaining denatured proteins in solution.

Differential detergent fractionation of cells is a rapid method for extraction of cytoplasmic and nuclear proteins in preparation of an immunoprecipitation. This method can be applied for use of adherent or suspension cells and can significantly reduce nonspecific background in an immunoprecipitation by separation of cellular compartments into individual fractions. The lysis of cells by differential detergents permits the rapid extraction of proteins from the cytoplasm (digitonin), the cytoplasmic membranes, and organelles (Triton X-100), and nucleoplasm (Tween/DOC), facilitated through the use of distinct extraction buffers. Cytoplasmic and nuclear matrix proteins as well as DNA are left behind during the detergent-based extraction.

Purified RNA may need to be concentrated by precipitation for downstream applications. Precipitation of RNA with ethanol (or isopropanol) is the standard method to recover RNA from aqueous solutions.

We assess the dynamics of volatility spillovers among global systemically important banks (G-SIBs). We measure spillovers using vector-autoregressive models of range volatility of the equity prices of G-SIBs, together with machine learning methods. We then compare the size of these spillovers with the degree of systemic importance measured by the Basel Committee on Banking Supervision's G-SIB bucket designations.

Press release: CPMI report sets out considerations for developers of wholesale digital tokens, 12 December 2019

The Bank of Canada, the Bank of England, the Bank of Japan, the European Central Bank, the Sveriges Riksbank and the Swiss National Bank, together with the Bank for International Settlements (BIS), have created a group to share experiences as they assess the potential case for central bank digital currency (CBDC) in their home jurisdictions. (Press release, 21 January 2020)

Michigan officials are ordering a Flint hospital to take steps to reduce the risk of exposure to Legionella bacteria and Legionnaires' disease at the facility.

Publication by Mr Dimitar Radev, Governor of the Bulgarian National Bank, in the Quarterly Bulletin of the Association of Banks in Bulgaria, issue 61, March 2020.

The upcoming debate about whether to expand the urban boundary is one of the city's big issues this term. But instead of delaying it, the city's testing out a never-before-attempted democratic process. Should they?

Despite having no ice on which to perform, more than 40 figure skaters from nine countries will take part in a fundraiser Friday to help health care workers on the front lines battling the new coronavirus.

Visions 2020: Nydia Han and 6abc celebrates Asian Pacific American Heritage Month - 6abc  WPVI-TV

Decorate a guitar, skateboard, or bike to help veterans, foster children  AZFamily

Mathias Colomb Cree Nation is wondering why the federal government ignored their community's proposal for an emergency COVID-19 response space in favour of a Calgary company's. 

Matteo Tranchellini and Moreno Monti created a coffee table book called CHICken to showcase the natural beauty of the ubiquitous birds.

Karla Bell was outside an Orangeville hospital waiting to start her nursing shift when she heard a cry for help from a car in the parking lot. She ran up to find a woman in labour in the passenger seat. Natalie Kalata tells us the incredible story of how this baby was born.

Ontario reported its lowest new COVID-19 case count of the week on Saturday with 346 new confirmed cases of the virus. Meanwhile, the government has issued an emergency order allowing school board employees to be voluntarily redeployed to hospitals, long-term care homes, retirement homes and women's shelters.

The Citizens for an Accountable Mega Hospital Planning Process are in court trying to get leave to appeal a ruling that dismissed their appeal to the Local Planning Appeal Tribunal over the location of the mega-hospital.

Of the 58 people who have died due to COVID-19 in Windsor-Essex, 14 of them were patients at Windsor Regional Hospital's field hospital.