| 1. |
- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 2. |
- Lindskog, Maria, et al.
(författare)
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Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation
- 2006
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 2:9, s. 1045-1060
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Forskningsöversikt (refereegranskat)abstract
- Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.
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| 3. |
- Blackwell, Kim T., et al.
(författare)
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Molecular mechanisms underlying striatal synaptic plasticity : relevance chronic alcohol consumption and seeking
- 2019
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 49:6, s. 768-783
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Tidskriftsartikel (refereegranskat)abstract
- The striatum, the input structure of the basal ganglia, is a major site learning and memory for goal-directed actions and habit formation. iny projection neurons of the striatum integrate cortical, thalamic, d nigral inputs to learn associations, with cortico-striatal synaptic asticity as a learning mechanism. Signaling molecules implicated in naptic plasticity are altered in alcohol withdrawal, which may ntribute to overly strong learning and increased alcohol seeking and nsumption. To understand how interactions among signaling molecules oduce synaptic plasticity, we implemented a mechanistic model of gnaling pathways activated by dopamine D1 receptors, acetylcholine ceptors, and glutamate. We use our novel, computationally efficient mulator, NeuroRD, to simulate stochastic interactions both within and tween dendritic spines. Dopamine release during theta burst and 20-Hz imulation was extrapolated from fast-scan cyclic voltammetry data llected in mouse striatal slices. Our results show that the combined tivity of several key plasticity molecules correctly predicts the currence of either LTP, LTD, or no plasticity for numerous perimental protocols. To investigate spatial interactions, we imulate two spines, either adjacent or separated on a 20-mu m ndritic segment. Our results show that molecules underlying LTP hibit spatial specificity, whereas 2-arachidonoylglycerol exhibits a atially diffuse elevation. We also implement changes in NMDA ceptors, adenylyl cyclase, and G protein signaling that have been asured following chronic alcohol treatment. Simulations under these nditions suggest that the molecular changes can predict changes in naptic plasticity, thereby accounting for some aspects of alcohol use sorder.
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| 4. |
- Ekström, Andreas, 1979, et al.
(författare)
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Dynamic changes in scope for heart rate and cardiac autonomic control during warm acclimation in rainbow trout
- 2016
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Ingår i: Journal of Experimental Biology. - : The Company of Biologists. - 0022-0949 .- 1477-9145. ; 219:8, s. 1106-1109
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Tidskriftsartikel (refereegranskat)abstract
- Time course studies are critical for understanding regulatory mechanisms and temporal constraints in ectothermic animals acclimating to warmer temperatures. Therefore, we investigated the dynamics of heart rate and its neuro-humoral control in rainbow trout (Onchorhynchus mykiss L.) acclimating to 16 degrees C for 39 days after being acutely warmed from 9 degrees C. Resting heart rate was 39 beats min(-1) at 9 degrees C, and increased significantly when fish were acutely warmed to 16 degrees C (Q(10)=1.9), but then declined during acclimation (Q(10)=1.2 at day 39), mainly due to increased cholinergic inhibition while the intrinsic heart rate and adrenergic tone were little affected. Maximum heart rate also increased with warming, although a partial modest decrease occurred during the acclimation period. Consequently, heart rate scope exhibited a complex pattern with an initial increase with acute warming, followed by a steep decline and then a subsequent increase, which was primarily explained by cholinergic inhibition of resting heart rate.
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| 5. |
- Eriksson, Olivia, PhD, 1971-, et al.
(författare)
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Combining hypothesis- and data-driven neuroscience modeling in FAIR workflows
- 2022
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Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 11
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Forskningsöversikt (refereegranskat)abstract
- Modeling in neuroscience occurs at the intersection of different points of view and approaches. Typically, hypothesis-driven modeling brings a question into focus so that a model is constructed to investigate a specific hypothesis about how the system works or why certain phenomena are observed. Data-driven modeling, on the other hand, follows a more unbiased approach, with model construction informed by the computationally intensive use of data. At the same time, researchers employ models at different biological scales and at different levels of abstraction. Combining these models while validating them against experimental data increases understanding of the multiscale brain. However, a lack of interoperability, transparency, and reusability of both models and the workflows used to construct them creates barriers for the integration of models representing different biological scales and built using different modeling philosophies. We argue that the same imperatives that drive resources and policy for data - such as the FAIR (Findable, Accessible, Interoperable, Reusable) principles - also support the integration of different modeling approaches. The FAIR principles require that data be shared in formats that are Findable, Accessible, Interoperable, and Reusable. Applying these principles to models and modeling workflows, as well as the data used to constrain and validate them, would allow researchers to find, reuse, question, validate, and extend published models, regardless of whether they are implemented phenomenologically or mechanistically, as a few equations or as a multiscale, hierarchical system. To illustrate these ideas, we use a classical synaptic plasticity model, the Bienenstock-Cooper-Munro rule, as an example due to its long history, different levels of abstraction, and implementation at many scales.
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| 6. |
- Hellgren, Olof, et al.
(författare)
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Global phylogeography of the avian malaria pathogen Plasmodium relictum based on MSP1 allelic diversity
- 2015
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Ingår i: Ecography. - : Wiley. - 1600-0587 .- 0906-7590. ; 38:8, s. 842-850
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Tidskriftsartikel (refereegranskat)abstract
- Knowing the genetic variation that occurs in pathogen populations and how it is distributed across geographical areas is essential to understand parasite epidemiology, local patterns of virulence, and evolution of host-resistance. In addition, it is important to identify populations of pathogens that are evolutionarily independent and thus free' to adapt to hosts and environments. Here, we investigated genetic variation in the globally distributed, highly invasive avian malaria parasite Plasmodium relictum, which has several distinctive mitochondrial haplotyps (cyt b lineages, SGS1, GRW11 and GRW4). The phylogeography of P. relictum was accessed using the highly variable nuclear gene merozoite surface protein 1 (MSP1), a gene linked to the invasion biology of the parasite. We show that the lineage GRW4 is evolutionarily independent of GRW11 and SGS1 whereas GRW11 and SGS1 share MSP1 alleles and thus suggesting the presence of two distinct species (GRW4 versus SGS1 and GRW11). Further, there were significant differences in the global distribution of MSP1 alleles with differences between GRW4 alleles in the New and the Old World. For SGS1, a lineage formerly believed to have both tropical and temperate transmission, there were clear differences in MSP1 alleles transmitted in tropical Africa compared to the temperate regions of Europe and Asia. Further, we highlight the occurrence of multiple MSP1 alleles in GRW4 isolates from the Hawaiian Islands, where the parasite has contributed to declines and extinctions of endemic forest birds since it was introduced. This study stresses the importance of multiple independent loci for understanding patterns of transmission and evolutionary independence across avian malaria parasites.
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| 7. |
- Hjorth, Johannes, et al.
(författare)
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GABAergic control of backpropagating action potentials in striatal medium spiny neurons
- 2008
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Konferensbidrag (refereegranskat)abstract
- Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites[1-3]. Increased calcium levels trigger changes in plasticity[4,5], which is important for learning and other functions[6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites[7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of these GABAergic inputs on the dendritic calcium dynamics is investigated.
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| 8. |
- Hjorth, Johannes, et al.
(författare)
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GABAergic control of dendritic calcium dynamics in striatal medium spiny neurons
- 2008
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Ingår i: Frontiers in Neuroinformatics. - : Frontiers Media SA. - 1662-5196.
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Konferensbidrag (refereegranskat)abstract
- Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites [1, 2, 3]. Increased calcium levels trigger changes in plasticity [4, 5], which is important for learning and other functions [6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites [7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of GABAergic inputs on the dendritic calcium dynamics is investigated.
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| 9. |
- Hjorth, Johannes, et al.
(författare)
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Gap Junctions between Striatal Fast-Spiking Interneurons Regulate Spiking Activity and Synchronization as a Function of Cortical Activity
- 2009
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 29:16, s. 5276-5286
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Tidskriftsartikel (refereegranskat)abstract
- Striatal fast-spiking (FS) interneurons are interconnected by gap junctions into sparsely connected networks. As demonstrated for cortical FS interneurons, these gap junctions in the striatum may cause synchronized spiking, which would increase the influence that FS neurons have on spiking by the striatal medium spiny (MS) neurons. Dysfunction of the basal ganglia is characterized by changes in synchrony or periodicity, thus gap junctions between FS interneurons may modulate synchrony and thereby influence behavior such as reward learning and motor control. To explore the roles of gap junctions on activity and spike synchronization in a striatal FS population, we built a network model of FS interneurons. Each FS connects to 30-40% of its neighbors, as found experimentally, and each FS interneuron in the network is activated by simulated corticostriatal synaptic inputs. Our simulations show that the proportion of synchronous spikes in FS networks with gap junctions increases with increased conductance of the electrical synapse; however, the synchronization effects are moderate for experimentally estimated conductances. Instead, the main tendency is that the presence of gap junctions reduces the total number of spikes generated in response to synaptic inputs in the network. The reduction in spike firing is due to shunting through the gap junctions; which is minimized or absent when the neurons receive coincident inputs. Together these findings suggest that a population of electrically coupled FS interneurons may function collectively as input detectors that are especially sensitive to synchronized synaptic inputs received from the cortex.
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| 10. |
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