| 1. |
- Brunet-Ratnasingham, Elsa, et al.
(författare)
-
Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity
- 2023
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized COVID-19 patients. Integrated analysis using k-means reveal four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors are delineated by high and low antibody responses. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the “Interferon paradox” previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.
|
|
| 2. |
- Brunet-Ratnasingham, Elsa, et al.
(författare)
-
Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity.
- 2024
-
Ingår i: Nature Communications. - 2041-1723. ; 15:1, s. 4177-
-
Tidskriftsartikel (refereegranskat)abstract
- Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.
|
|
| 3. |
- Cruz, Raquel, et al.
(författare)
-
Novel genes and sex differences in COVID-19 severity
- 2022
-
Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
-
Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
|
|
| 4. |
- Elinder, Fredrik, et al.
(författare)
-
Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1
- 2016
-
Ingår i: Biophysical Journal. - : CELL PRESS. - 0006-3495 .- 1542-0086. ; 111:8, s. 1679-1691
-
Tidskriftsartikel (refereegranskat)abstract
- The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels voltage dependences to a large extent are set by charged amino-acid residues of the extracellular linkers of the Kv channels, which electrostatically affect the charged amino-acid residues of the voltage sensor S4. Extracellular cations shift the conductance-versus-voltage curve, G(V), by interfering with these extracellular charges. We have explored these issues by analyzing the effects of the divalent strontium ion (Sr2+) on the voltage dependence of the G(V) curves of wild-type and chimeric Kv channels expressed in Xenopus oocytes, using the voltage-clamp technique. Out of seven Kv channels, Kv1.2 was found to be most sensitive to Sr2+ (50 mM shifted G(V) by +21.7 mV), and Kv2.1 to be the least sensitive (+7.8 mV). Experiments on 25 chimeras, constructed from Kv1.2 and Kv2.1, showed that the large Sr2+-induced G(V) shift of Kv1.2 can be transferred to Kv2.1 by exchanging the extracellular linker between S3 and S4 (L3/4) in combination with either the extracellular linker between S5 and the pore (L5/P) or that between the pore and S6 (LP/6). The effects of the linker substitutions were nonadditive, suggesting specific structural interactions. The free energy of these interactions was similar to 20 kJ/mol, suggesting involvement of hydrophobic interactions and/or hydrogen bonds. Using principles from double-layer theory we derived an approximate linear equation (relating the voltage shifts to altered ionic strength), which proved to well match experimental data, suggesting that Sr2+ acts on these channels mainly by screening surface charges. Taken together, these results highlight the extracellular surface potential at the voltage sensor as an important determinant of the channels voltage dependence, making the extracellular linkers essential targets for evolutionary selection.
|
|
| 5. |
- Fahlström, Andreas, et al.
(författare)
-
A grading scale for surgically treated patients with spontaneous supratentorial intracerebral hemorrhage : The Surgical Swedish ICH Score
- 2020
-
Ingår i: Journal of Neurosurgery. - Rolling Meadows, IL United States : American Association of Neurological Surgeons. - 0022-3085 .- 1933-0693. ; 133:3, s. 800-807
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE The authors aimed to develop the first clinical grading scale for patients with surgically treated spontaneous supratentorial intracerebral hemorrhage (ICH). METHODS A nationwide multicenter study including 401 ICH patients surgically treated by craniotomy and evacuation of a spontaneous supratentorial ICH was conducted between January 1, 2011, and December 31, 2015. All neurosurgical centers in Sweden were included. All medical records and neuroimaging studies were retrospectively reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the Surgical Swedish ICH [SwICH] Score) was developed using weighting of independent predictors based on strength of association. RESULTS Factors independently associated with 30-day mortality were Glasgow Coma Scale (GCS) score (p = 0.00015), ICH volume ≥ 50 mL (p = 0.031), patient age ≥ 75 years (p = 0.0056), prior myocardial infarction (MI) (p = 0.00081), and type 2 diabetes (p = 0.0093). The Surgical SwICH Score was the sum of individual points assigned as follows: GCS score 15–13 (0 points), 12–5 (1 point), 4–3 (2 points); age ≥ 75 years (1 point); ICH volume ≥ 50 mL (1 point); type 2 diabetes (1 point); prior MI (1 point). Each increase in the Surgical SwICH Score was associated with a progressively increased 30-day mortality (p = 0.0002). No patient with a Surgical SwICH Score of 0 died, whereas the 30-day mortality rates for patients with Surgical SwICH Scores of 1, 2, 3, and 4 were 5%, 12%, 31%, and 58%, respectively. CONCLUSIONS The Surgical SwICH Score is a predictor of 30-day mortality in patients treated surgically for spontaneous supratentorial ICH. External validation is needed to assess the predictive value as well as the generalizability of the Surgical SwICH Score.
|
|
| 6. |
- Fallerini, Chiara, et al.
(författare)
-
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
- 2022
-
Ingår i: Human Genetics. - : Springer Nature. - 0340-6717 .- 1432-1203. ; 141:1, s. 147-173
-
Tidskriftsartikel (refereegranskat)abstract
- The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.
|
|
| 7. |
|
|
| 8. |
- Nakanishi, Tomoko, et al.
(författare)
-
Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
- 2021
-
Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 131:23
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. There is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition. METHODS. We combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank. RESULTS. We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors. CONCLUSIONS. The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.
|
|
| 9. |
- Petersen, Julian, et al.
(författare)
-
A previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- In this study we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, we identify gene flow of FAME from Neandertals into modern humans. We conduct knockout experiments on animals and observe altered body weight and decreased energy expenditure in Fame knockout animals, corresponding to genome-wide association studies linking FAME with higher body mass index in humans. Gene expression and subcellular localization analyses reveal that FAME is a membrane-bound protein enriched in the kidneys. Although the gene knockout results in structurally normal kidneys, we detect higher albumin in urine and lowered ferritin in the blood. Through experimental validation, we confirm interactions between FAME and ferritin and show co-localization in vesicular and plasma membranes.
|
|
| 10. |
- Pettersson, Anna F., et al.
(författare)
-
How students discern anatomical structures using digital three-dimensional visualizations in anatomy education
- 2023
-
Ingår i: Anatomical sciences education. - : John Wiley & Sons. - 1935-9772 .- 1935-9780. ; 16:3, s. 452-464
-
Tidskriftsartikel (refereegranskat)abstract
- Learning anatomy holds specific challenges, like the appreciation of three-dimensional relationships between anatomical structures. So far, there is limited knowledge about how students construct their understanding of topographic anatomy. By understanding the processes by which students learn anatomical structures in 3D, educators will be better equipped to offer support and create successful learning situations. Using video analysis, this study investigates how students discern anatomical structures. Sixteen students at different levels of education and from different study programs were recorded audiovisually while exploring 3D digital images using a computerized visualization table. Eleven hours of recorded material were analyzed using interaction analysis and phenomenography. Seven categories were identified during data analysis, describing the qualitatively different patterns of actions that students use to make sense of anatomy: decoding the image; positioning the body in space; purposeful seeking, using knowledge and experience; making use of and creating variation; aimless exploration, and arriving at moments of understanding. The results suggest that anatomy instruction should be organized to let the students decide how and at what pace they examine visualized images. Particularly, the discovery process of decoding and positioning the body in space supports a deep learning approach for learning anatomy using visualizations. The students' activities should be facilitated and not directed.
|
|
| 11. |
- Silén, Charlotte, et al.
(författare)
-
Three-dimensional visualisation of authentic cases in anatomy learning : An educational design study
- 2022
-
Ingår i: BMC Medical Education. - : BioMed Central. - 1472-6920. ; 22:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many studies have investigated the value of three-dimensional (3D) images in learning anatomy. However, there is a lack of knowledge about students learning processes using technology and 3D images. To understand how to facilitate and support the learning of anatomy, there is a need to know more about the student perspectives on how they can use and benefit from 3D images.METHODS: This study used designed educational sessions informed by Educational Design Research to investigate the role of technology-enhanced 3D images in students' anatomy learning. Twenty-four students representing different health professions and multiple study levels, and one tutor, participated in the study. A visualisation table was used to display the images of real patient cases related to disorders associated with the abdomen and the brain. Students were asked to explore the images on their own and audio/video capture was used to record their words and actions. Directly following the session, students were interviewed about their perceptions and different ways of learning and studying anatomy. The tutor was interviewed about his reflections on the session and his role as a facilitator on two occasions. Content analysis was used in its manifest and latent form in the data analysis.RESULT: Two main categories describing the students' and tutor's accounts of learning using the visualisation table were identified: 1. Interpreting 3D images and 2. Educational sessions using visualisation tables. Each category had signifying themes representing interpretations of the latent meaning of the students' and tutor's accounts. These were: Realism and complexity; Processes of discernment; References to previous knowledge; Exploring on one's own is valuable; Context enhances learning experiences; Combinations of learning resources are needed and Working together affects the dynamics.CONCLUSIONS: This study identifies several important factors to be considered when designing effective and rewarding educational sessions using a visualization table and 3D images in anatomy education. Visualisation of authentic images has the potential to create interest and meaningfulness in studying anatomy. Students need time to actively explore images but also get tutor guidance to understand. Also, a combination of different resources comprises a more helpful whole than a single learning resource.
|
|
| 12. |
- Xie, Meng, et al.
(författare)
-
The level of protein in the maternal murine diet modulates the facial appearance of the offspring via mTORC1 signaling.
- 2024
-
Ingår i: Nature communications. - 2041-1723. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- The development of craniofacial skeletal structures is fascinatingly complex and elucidation of the underlying mechanisms will not only provide novel scientific insights, but also help develop more effective clinical approaches to the treatment and/or prevention of the numerous congenital craniofacial malformations. To this end, we performed a genome-wide analysis of RNA transcription from non-coding regulatory elements by CAGE-sequencing of the facial mesenchyme of human embryos and cross-checked the active enhancers thus identified against genes, identified by GWAS for the normal range human facial appearance. Among the identified active cis-enhancers, several belonged to the components of the PI3/AKT/mTORC1/autophagy pathway. To assess the functional role of this pathway, we manipulated it both genetically and pharmacologically in mice and zebrafish. These experiments revealed that mTORC1 signaling modulates craniofacial shaping at the stage of skeletal mesenchymal condensations, with subsequent fine-tuning during clonal intercalation. This ability of mTORC1 pathway to modulate facial shaping, along with its evolutionary conservation and ability to sense external stimuli, in particular dietary amino acids, indicate that the mTORC1 pathway may play a role in facial phenotypic plasticity. Indeed, the level of protein in the diet of pregnant female mice influenced the activity of mTORC1 in fetal craniofacial structures and altered the size of skeletogenic clones, thus exerting an impact on the local geometry and craniofacial shaping. Overall, our findings indicate that the mTORC1 signaling pathway is involved in the effect of environmental conditions on the shaping of craniofacial structures.
|
|
| 13. |
- Yoshiji, Satoshi, et al.
(författare)
-
Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity
- 2023
-
Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5, s. 248-264
-
Tidskriftsartikel (refereegranskat)abstract
- How obesity contributes to COVID-19 severity is not fully understood. In this study, Yoshiji et al. found that the plasma protein nephronectin partially mediates the effect of obesity on the risk of COVID-19 severity using a two-step Mendelian randomization approach and omics analyses. Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 x 10(-10)). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.
|
|
| 14. |
- Zeberg, Hugo, et al.
(författare)
-
A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans
- 2020
-
Ingår i: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 30:17, s. 3465-3469
-
Tidskriftsartikel (refereegranskat)abstract
- The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.
|
|
| 15. |
- Zeberg, Hugo
(författare)
-
Conductance-based principles of neuronal firing and excitability
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The brain is an electrical organ whose activity is determined by the flow of ions across cell membranes. As such, the conductances that control the ion flux is a key to our understanding of the nervous system. Neurons process information by their ability to rapidly depolarize and fire action potentials. With the help of dynamical systems theory we have analysed the mechanisms behind this excitability. Specifically, we have used bifurcations theory to characterize the different dynamical pathways that lead to repetitive action potentials, or in terms of dynamical systems, to the emergence of limit cycles. We have demonstrated how downand up-regulation of various conductances (e.g., potassium current) lead to altered firing patterns and altered threshold dynamics. Crudely, electrical activity in nerve cells can be classified in two main classes: resonators and integrators. It was previously believed that certain channels were needed for the different types, but we have shown that in many cases it is sufficient to change the native conductances to alter class. Using the dynamic clamp technique we have also tested this hypothesis in-vivo. By artificially increasing the potassium conductance in pyramidal cells in rat cortex we were able to demonstrate a shift in dynamical type. Moreover, we have analysed synapse conductances between interneurons in neocortex. In particular, we have investigated fast-spiking interneurons, which recently were shown to be responsible for the generation of gamma oscillation (30-80 Hz). These neurons are interconnected by a combined chemical-electrical synapse. To understand how these synaptic interactions control synchronous firing, artificial synaptic conductances were injected into fast-spiking cells. Using standard techniques from synchronization theory, such as the phase response curve, we showed how this combined synapse is especially suited for entrainment over a wide gamma frequency band, whose upper and lower frequency limits are given by the electrical component and the inhibitory chemical component, respectively. Conductances can also be studied at an ion channel level. We examined how local anesthetics block ion channel conductance by binding to the ion channel in an open state. This state-dependent block was analysing in terms of Markov-chains and mathematical formulae for the open probability under voltage-clamp were derived. This knowledge might be valuable for developing new principles for pharmacological treatment. Theories must be tested against reality. The so-called dynamic-clamp technique allows mathematical models to be directly integrated using a real-time interface with living cells - a hybrid circuit is created between a computer and a nerve cell. The equations for the currents that one wishes to examine are simulated in a computer. The membrane potential is sampled and the current that would be passed through these artificial channels is injected into the cell, whereupon the voltage change and the current is calculated and injected again. The time scales are so short that this cycle must be performed within tens of microseconds. One problem with the dynamic clamp protocol has been the integration method used. We solved this issue by introducing a stable implicit Runge-Kutta method suited for stiff equations. Understanding the inherent dynamics of different neuron types and their interplay with network activity is essential for understanding complex processes such as altered awareness levels caused by general anesthesia and psychopharmacological interventions. It is the hope that the findings in this thesis may add a small piece to the puzzle of understanding normal as well as pathological brain function.
|
|
| 16. |
- Zeberg, Hugo, et al.
(författare)
-
Ion Channel Density Regulates Switches between Regular and Fast Spiking in Soma but Not in Axons
- 2010
-
Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 6:4, s. e1000753-
-
Tidskriftsartikel (refereegranskat)abstract
- The threshold firing frequency of a neuron is a characterizing feature of its dynamical behaviour, in turn determining its role in the oscillatory activity of the brain. Two main types of dynamics have been identified in brain neurons. Type 1 dynamics (regular spiking) shows a continuous relationship between frequency and stimulation current (f-I-stim) and, thus, an arbitrarily low frequency at threshold current; Type 2 (fast spiking) shows a discontinuous f-I-stim relationship and a minimum threshold frequency. In a previous study of a hippocampal neuron model, we demonstrated that its dynamics could be of both Type 1 and Type 2, depending on ion channel density. In the present study we analyse the effect of varying channel density on threshold firing frequency on two well-studied axon membranes, namely the frog myelinated axon and the squid giant axon. Moreover, we analyse the hippocampal neuron model in more detail. The models are all based on voltage-clamp studies, thus comprising experimentally measurable parameters. The choice of analysing effects of channel density modifications is due to their physiological and pharmacological relevance. We show, using bifurcation analysis, that both axon models display exclusively Type 2 dynamics, independently of ion channel density. Nevertheless, both models have a region in the channel-density plane characterized by an N-shaped steady-state current-voltage relationship (a prerequisite for Type 1 dynamics and associated with this type of dynamics in the hippocampal model). In summary, our results suggest that the hippocampal soma and the two axon membranes represent two distinct kinds of membranes; membranes with a channel-density dependent switching between Type 1 and 2 dynamics, and membranes with a channel-density independent dynamics. The difference between the two membrane types suggests functional differences, compatible with a more flexible role of the soma membrane than that of the axon membrane.
|
|
| 17. |
|
|
| 18. |
- Zhou, Sirui, et al.
(författare)
-
A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity
- 2021
-
Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 27:4, s. 659-667
-
Tidskriftsartikel (refereegranskat)abstract
- To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.
|
|
| 19. |
- Ågren, Richard, et al.
(författare)
-
Dopamine d2 receptor agonist binding kinetics : role of a conserved serine residue
- 2021
-
Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:8
-
Tidskriftsartikel (refereegranskat)abstract
- The forward (kon) and reverse (koff ) rate constants of drug–target interactions have important implications for therapeutic efficacy. Hence, time-resolved assays capable of measuring these binding rate constants may be informative to drug discovery efforts. Here, we used an ion channel activation assay to estimate the kons and koff s of four dopamine D2 receptor (D2R) ago-nists; dopamine (DA), p-tyramine, (R)-and (S)-5-OH-dipropylaminotetralin (DPAT). We further probed the role of the conserved serine S1935.42 by mutagenesis, taking advantage of the preferential interaction of (S)-, but not (R)-5-OH-DPAT with this residue. Results suggested similar koff s for the two 5-OH-DPAT enantiomers at wild-type (WT) D2R, both being slower than the koff s of DA and p-tyramine. Conversely, the kon of (S)-5-OH-DPAT was estimated to be higher than that of (R)-5-OH-DPAT, in agreement with the higher potency of the (S)-enantiomer. Furthermore, S1935.42A mutation lowered the kon of (S)-5-OH-DPAT and reduced the potency difference between the two 5-OH-DPAT enantiomers. Kinetic Kds derived from the koff and kon estimates correlated well with EC50 values for all four compounds across four orders of magnitude, strengthening the notion that our assay captured meaningful information about binding kinetics. The approach presented here may thus prove valuable for characterizing D2R agonist candidate drugs.
|
|
| 20. |
- Ågren, Richard, et al.
(författare)
-
In vitro comparison of ulotaront (SEP-363856) and ralmitaront (RO6889450) : two TAAR1 agonist candidate antipsychotics
- 2023
-
Ingår i: International Journal of Neuropsychopharmacology. - : Oxford University Press. - 1461-1457 .- 1469-5111. ; 26:9, s. 599-606
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront.METHODS: We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein-coupled inward rectifier potassium channel activation assays.RESULTS: Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2.CONCLUSIONS: Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds.
|
|
| 21. |
- Ågren, Richard, et al.
(författare)
-
Ligand with Two Modes of Interaction with the Dopamine D-2 Receptor-An Induced-Fit Mechanism of Insurmountable Antagonism
- 2020
-
Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 11:19, s. 3130-3143
-
Tidskriftsartikel (refereegranskat)abstract
- A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D2 receptor (D2R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D2R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), whereas recovery was less prominent (∼20%) upon washout of the 4-carbon linker compound, SV-III-130, both with 1 and 100 μM DA. Prolonging the coincubation time with SV-III-130 further diminished recovery. Curve-shift experiments were consistent with competition between SV-III-130 and DA. Two mutations in the secondary binding pocket (V91A and E95A) of D2R decreased antagonistic potency and increased recovery from SV-III-130 antagonism, whereas a third mutation (L94A) only increased recovery. Our results suggest that the secondary binding pocket influences recovery from inhibition by the studied aripiprazole analogues. We propose a mechanism, supported by in silico modeling, whereby SV-III-130 initially binds reversibly to the D2R, after which the drug-receptor complex undergoes a slow transition to a second ligand-bound state, which is dependent on secondary binding pocket integrity and irreversible during the time frame of our experiments.
|
|
| 22. |
- Ågren, Richard, et al.
(författare)
-
Major genetic risk factors for Dupuytren's disease are inherited from neandertals
- 2023
-
Ingår i: Molecular biology and evolution. - : Oxford University Press. - 0737-4038 .- 1537-1719. ; 40:6
-
Tidskriftsartikel (refereegranskat)abstract
- Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the second and third most strongly associated ones (P = 6.4 × 10-132 and P = 9.2 × 10-69, respectively). For the most strongly associated Neandertal variant, we identify EPDR1 as the causal gene. Dupuytren's disease is an example of how admixture with Neandertals has shaped regional differences in disease prevalence.
|
|
