| 1. |
- Bott, Lukas Thomas, et al.
(författare)
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Coulomb dissociation of O-16 into He-4 and C-12
- 2023
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Ingår i: NUCLEAR PHYSICS IN ASTROPHYSICS - X, NPA-X 2022. - : EDP Sciences. - 2100-014X. ; 279
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Konferensbidrag (refereegranskat)abstract
- We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4.
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| 2. |
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| 3. |
- Dekkers, Koen, et al.
(författare)
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An online atlas of human plasma metabolite signatures of gut microbiome composition.
- 2022
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 58% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas ( https://gutsyatlas.serve.scilifelab.se/ ). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition.
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| 4. |
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| 5. |
- Demurtas, Jacopo, et al.
(författare)
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Physical Activity and Exercise in Mild Cognitive Impairment and Dementia : An Umbrella Review of Intervention and Observational Studies
- 2020
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610 .- 1538-9375. ; 21:10, s. 1415-1422
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Forskningsöversikt (refereegranskat)abstract
- Objectives: The aim of this umbrella review was to determine the effect of physical activity/exercise on improving cognitive and noncognitive outcomes in people with MCI (mild cognitive impairment) and dementia.Design: Umbrella review of systematic reviews (SR), with or without meta-analyses (MAs), of randomized controlled trials (RCTs) and observational studies.Settings and Participants: People with MCI or dementia, confirmed through validated assessment measures. Any form of physical activity/exercise was included. As controls, we included participants not following any prespecified physical activity/exercise intervention or following the same standard protocol with the intervention group.Methods: The protocol was registered in PROSPERO (CDR 164197). Major databases were searched until December 31, 2019. The certainty of evidence of statistically significant outcomes was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. SRs' findings, without a formal MA, were reported descriptively.Results: Among 1160 articles initially evaluated, 27 SRs (all of RCTs, 9 without MA) for a total of 28,205 participants with MCI/dementia were included. In patients with MCI, mind-body intervention (standardized mean difference [SMD] = 0.36; 95% confidence intervals [CI] 0.20-0.52; low certainty) and mixed physical activity interventions (SMD = 0.30; 95% CI 0.11-0.49; moderate certainty) had a small effect on global cognition, whereas resistance training (SMD = 0.80; 95% CI 0.29-1.31; very low certainty) had a large effect on global cognition. In people affected by dementia, physical activity/exercise was effective in improving global cognition in Alzheimer disease (SMD = 1.10; 95% CI 0.65-1.64; very low certainty) and in all types of dementia (SMD = 0.48; 95% CI 0.22-0.74; low certainty). Finally, physical activity/exercise improved noncognitive outcomes in people with dementia including falls, and neuropsychiatric symptoms.Conclusions and Implications: Supported by very low-to-moderate certainty of evidence, physical activity/exercise has a positive effect on several cognitive and noncognitive outcomes in people with MCI and dementia, but RCTs, with low risk of bias/confounding, are still needed to confirm these relationships.
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| 6. |
- Dura, Alexandru, et al.
(författare)
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Clog : A Declarative Language for C Static Code Checkers
- 2024
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Ingår i: CC 2024 - Proceedings of the 33rd ACM SIGPLAN International Conference on Compiler Construction. - 9798400705076 ; , s. 186-197
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Konferensbidrag (refereegranskat)abstract
- We present Clog, a declarative language for describing static code checkers for C. Unlike other extensible state-of-the-art checker frameworks, Clog enables powerful interprocedural checkers without exposing the underlying program representation: Clog checkers consist of Datalog-style recursive rules that access the program under analysis via syntactic pattern matching and control flow edges only. We have implemented Clog on top of Clang, using a custom Datalog evaluation strategy that piggy-backs on Clang’s AST matching facilities while working around Clang’s limitations to achieve our design goal of representation independence. Our experiments demonstrate that Clog can concisely express a wide variety of checkers for different security vulnerabilities, with performance that is similar to Clang’s own analyses and highly competitive on real-world programs.
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| 7. |
- Ernst, Chantal, et al.
(författare)
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Direct Salmonella injection into enteroid cells allows the study of host-pathogen interactions in the cytosol with high spatiotemporal resolution
- 2024
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 22:4
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal epithelial cells (IECs) play pivotal roles in nutrient uptake and in the protection against gut microorganisms. However, certain enteric pathogens, such as Salmonella enterica serovar Typhimurium (S. Tm), can invade IECs by employing flagella and type III secretion systems (T3SSs) with cognate effector proteins and exploit IECs as a replicative niche. Detection of flagella or T3SS proteins by IECs results in rapid host cell responses, i.e., the activation of inflammasomes. Here, we introduce a single-cell manipulation technology based on fluidic force microscopy (FluidFM) that enables direct bacteria delivery into the cytosol of single IECs within a murine enteroid monolayer. This approach allows to specifically study pathogen-host cell interactions in the cytosol uncoupled from preceding events such as docking, initiation of uptake, or vacuole escape. Consistent with current understanding, we show using a live-cell inflammasome reporter that exposure of the IEC cytosol to S. Tm induces NAIP/NLRC4 inflammasomes via its known ligands flagellin and T3SS rod and needle. Injected S. Tm mutants devoid of these invasion-relevant ligands were able to grow in the cytosol of IECs despite the absence of T3SS functions, suggesting that, in the absence of NAIP/NLRC4 inflammasome activation and the ensuing cell death, no effector-mediated host cell manipulation is required to render the epithelial cytosol growth-permissive for S. Tm. Overall, the experimental system to introduce S. Tm into single enteroid cells enables investigations into the molecular basis governing host-pathogen interactions in the cytosol with high spatiotemporal resolution.
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| 8. |
- Goodwin, Christopher M., 1989-, et al.
(författare)
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Operando Probing of the Surface Chemistry During the Haber-Bosch Process
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 282-286
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Tidskriftsartikel (refereegranskat)abstract
- The Haber-Bosch process produces NH3 from N2 and H21,2, typically with Fe and Ru3. HB has been proposed as the most important scientific invention in the 20th century4. The chemical state during reaction has been proposed as oxides5, nitrides2, metallic, or surface nitride6. The proposed rate-limiting step has been the dissociation of N27–9, reaction of adsorbed nitrogen10, or desorption of NH311. Due to the vacuum requirement for surface-sensitive techniques, studies at reaction conditions are limited to theory computations12–14. We determined the surface composition, during NH3 production, at pressures up to 1 bar and temperatures as high as 723 K on flat, stepped Fe, and stepped Ru single crystal surfaces using operando X-ray Photoelectron Spectroscopy15. We found that all surfaces remain metallic. On Fe only a small amount of adsorbed N remains, yet Ru’s surface is almost adsorbate free. At 523 K, high amines (NHx) coverages appear on the stepped Fe surface. The results show that the rate-limiting step on Ru is always N2 dissociation. Still, on Fe the hydrogenation step involving adsorbed N atoms is essential for the total rate, as predicted by theory13. If the temperature is lowered on Fe, the rate-limiting steps switch and become surface species’ hydrogenation.
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| 9. |
- Grossmann, Igor, et al.
(författare)
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Insights into the accuracy of social scientists' forecasts of societal change
- 2023
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Ingår i: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 7, s. 484-501
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Tidskriftsartikel (refereegranskat)abstract
- How well can social scientists predict societal change, and what processes underlie their predictions? To answer these questions, we ran two forecasting tournaments testing the accuracy of predictions of societal change in domains commonly studied in the social sciences: ideological preferences, political polarization, life satisfaction, sentiment on social media, and gender-career and racial bias. After we provided them with historical trend data on the relevant domain, social scientists submitted pre-registered monthly forecasts for a year (Tournament 1; N = 86 teams and 359 forecasts), with an opportunity to update forecasts on the basis of new data six months later (Tournament 2; N = 120 teams and 546 forecasts). Benchmarking forecasting accuracy revealed that social scientists' forecasts were on average no more accurate than those of simple statistical models (historical means, random walks or linear regressions) or the aggregate forecasts of a sample from the general public (N = 802). However, scientists were more accurate if they had scientific expertise in a prediction domain, were interdisciplinary, used simpler models and based predictions on prior data. How accurate are social scientists in predicting societal change, and what processes underlie their predictions? Grossmann et al. report the findings of two forecasting tournaments. Social scientists' forecasts were on average no more accurate than those of simple statistical models.
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| 10. |
- Jones, Benedict C, et al.
(författare)
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To which world regions does the valence-dominance model of social perception apply?
- 2021
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Ingår i: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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| 11. |
- Kamundala, Gabriel
(creator_code:cre_t)
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Kamituga I Digital Gold
- 2022
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Konstnärligt arbete (övrigt vetenskapligt/konstnärligt)abstract
- This is one exhibition room within the larger "Planet Digital" exhibition (https://www.planetdigital.ch/en) hosted by the Museum für Gestaltung, Zürich, Switzerland (20.2.2022 to 6.6.2022).
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| 12. |
- Kreisz, Philipp, et al.
(författare)
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S1 basic leucine zipper transcription factors shape plant architecture by controlling C/N partitioning to apical and lateral organs
- 2024
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 121:7
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Tidskriftsartikel (refereegranskat)abstract
- Plants tightly control growth of their lateral organs, which led to the concept of apical dominance. However, outgrowth of the dormant lateral primordia is sensitive to the plant's nutritional status, resulting in an immense plasticity in plant architecture. While the impact of hormonal regulation on apical dominance is well characterized, the prime importance of sugar signaling to unleash lateral organ formation has just recently emerged. Here, we aimed to identify transcriptional regulators, which control the trade-off between growth of apical versus lateral organs. Making use of locally inducible gain-of-function as well as single and higher-order loss-of-function approaches of the sugar-responsive S1-basic-leucine-zipper (S1-bZIP) transcription factors, we disclosed their largely redundant function in establishing apical growth dominance. Consistently, comprehensive phenotypical and analytical studies of S1-bZIP mutants show a clear shift of sugar and organic nitrogen (N) allocation from apical to lateral organs, coinciding with strong lateral organ outgrowth. Tissue-specific transcriptomics reveal specific clade III SWEET sugar transporters, crucial for long-distance sugar transport to apical sinks and the glutaminase GLUTAMINE AMIDO-TRANSFERASE 1_2.1, involved in N homeostasis, as direct S1-bZIP targets, linking the architectural and metabolic mutant phenotypes to downstream gene regulation. Based on these results, we propose that S1-bZIPs control carbohydrate (C) partitioning from source leaves to apical organs and tune systemic N supply to restrict lateral organ formation by C/N depletion. Knowledge of the underlying mechanisms controlling plant C/N partitioning is of pivotal importance for breeding strategies to generate plants with desired architectural and nutritional characteristics.
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| 13. |
- Milosevic, Jelena, et al.
(författare)
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PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms.Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.
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| 14. |
- Motos, Ghislain, et al.
(författare)
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Aerosol and dynamical contributions to cloud droplet formation in Arctic low-level clouds
- 2023
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Ingår i: Atmospheric Chemistry And Physics. - 1680-7316 .- 1680-7324. ; 23:21, s. 13941-13956
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Tidskriftsartikel (refereegranskat)abstract
- The Arctic is one of the most rapidly warming regions of the globe. Low-level clouds and fog modify the energy transfer from and to space and play a key role in the observed strong Arctic surface warming, a phenomenon commonly termed “Arctic amplification”. The response of low-level clouds to changing aerosol characteristics throughout the year is therefore an important driver of Arctic change that currently lacks sufficient constraints. As such, during the NASCENT campaign (Ny-Ålesund AeroSol Cloud ExperimeNT) extending over a full year from October 2019 to October 2020, microphysical properties of aerosols and clouds were studied at the Zeppelin station (475 m a.s.l.), Ny-Ålesund, Svalbard, Norway. Particle number size distributions obtained from differential mobility particle sizers as well as chemical composition derived from filter samples and an aerosol chemical speciation monitor were analyzed together with meteorological data, in particular vertical wind velocity. The results were used as input to a state-of-the-art cloud droplet formation parameterization to investigate the particle sizes that can activate to cloud droplets, the levels of supersaturation that can develop, the droplet susceptibility to aerosol and the role of vertical velocity. We evaluate the parameterization and the droplet numbers calculated through a droplet closure with in-cloud in situ measurements taken during nine flights over 4 d. A remarkable finding is that, for the clouds sampled in situ, closure is successful in mixed-phase cloud conditions regardless of the cloud glaciation fraction. This suggests that ice production through ice–ice collisions or droplet shattering may have explained the high ice fraction, as opposed to rime splintering that would have significantly reduced the cloud droplet number below levels predicted by warm-cloud activation theory. We also show that pristine-like conditions during fall led to clouds that formed over an aerosol-limited regime, with high levels of supersaturation (generally around 1 %, although highly variable) that activate particles smaller than 20 nm in diameter. Clouds formed in the same regime in late spring and summer, but aerosol activation diameters were much larger due to lower cloud supersaturations (ca. 0.5 %) that develop because of higher aerosol concentrations and lower vertical velocities. The contribution of new particle formation to cloud formation was therefore strongly limited, at least until these newly formed particles started growing. However, clouds forming during the Arctic haze period (winter and early spring) can be limited by updraft velocity, although rarely, with supersaturation levels dropping below 0.1 % and generally activating larger particles (20 to 200 nm), including pollution transported over a long range. The relationship between updraft velocity and the limiting cloud droplet number agrees with previous observations of various types of clouds worldwide, which supports the universality of this relationship.
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| 15. |
- Novik, Bengt, et al.
(författare)
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Association of Mesh and Fixation Options with Reoperation Risk after Laparoscopic Groin Hernia Surgery : A Swedish Hernia Registry Study of 25,190 Totally Extraperitoneal and Transabdominal Preperitoneal Repairs.
- 2022
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Ingår i: Journal of the American College of Surgeons. - 1072-7515 .- 1879-1190. ; 234:3, s. 311-325
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: International guidelines concerning mesh and mesh fixation options in laparoscopic totally extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) groin hernia repair are based on studies focusing on either mesh or fixation. We hypothesized that the value of such recommendations is limited by lacking knowledge on how mesh and fixation interact. The current registry-based nationwide cohort study compared different mesh/fixation combinations for relative risks for reoperation after TEP and TAPP groin hernia repair.STUDY DESIGN: All TEP and TAPP registered in the Swedish Hernia Registry 2005 to 2017 with standard polypropylene (StdPPM) or lightweight (LWM) flat mesh, having tack, fibrin glue, or no fixation, were included. The endpoint was reoperation due to recurrence as of December 31, 2018. Multivariable Cox regression rendered relative risk differences between the exposures, expressed as hazard ratios (HR) with 95% CIs.RESULTS: Of 25,190 repairs, 924 (3.7%) were later reoperated for recurrence. The lowest, mutually equivalent, reoperation risks were associated with StdPPM without fixation (HR 1), StdPPM with metal tacks (HR 0.8, CI 0.4 to 1.4), StdPPM with fibrin glue (HR 1.1, CI 0.7 to 1.6), and LWM with fibrin glue (HR 1.2, CI 0.97 to 1.6). Except for with fibrin glue, LWM correlated with increased risk, whether affixed with metal (HR 1.7, CI 1.1 to 2.7), or absorbable tacks (HR 2.4, CI 1.8 to 3.1), or deployed without fixation (HR 2.0, CI 1.6 to 2.6).CONCLUSIONS: With StdPPM, neither mechanical nor glue fixation seemed to improve outcomes. Thus, for this mesh category, we recommend nonfixation. With LWM, we recommend fibrin glue fixation, which was the only LWM alternative on par with nonaffixed StdPPM.
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| 16. |
- Nugroho, Ferry, 1986, et al.
(författare)
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Inverse designed plasmonic metasurface with parts per billion optical hydrogen detection
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasmonic sensors rely on optical resonances in metal nanoparticles and are typically limited by their broad spectral features. This constraint is particularly taxing for optical hydrogen sensors, in which hydrogen is absorbed inside optically-lossy Pd nanostructures and for which state-of-the-art detection limits are only at the low parts-per-million (ppm) range. Here, we overcome this limitation by inversely designing a plasmonic metasurface based on a periodic array of Pd nanoparticles. Guided by a particle swarm optimization algorithm, we numerically identify and experimentally demonstrate a sensor with an optimal balance between a narrow spectral linewidth and a large field enhancement inside the nanoparticles, enabling a measured hydrogen detection limit of 250 parts-per-billion (ppb). Our work significantly improves current plasmonic hydrogen sensor capabilities and, in a broader context, highlights the power of inverse design of plasmonic metasurfaces for ultrasensitive optical (gas) detection.
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| 17. |
- Schweiker, Marcel, et al.
(författare)
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Evaluating assumptions of scales for subjective assessment of thermal environments – Do laypersons perceive them the way, we researchers believe?
- 2020
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Ingår i: Energy and Buildings. - : Elsevier BV. - 0378-7788. ; 211
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Tidskriftsartikel (refereegranskat)abstract
- People's subjective response to any thermal environment is commonly investigated by using rating scales describing the degree of thermal sensation, comfort, and acceptability. Subsequent analyses of results collected in this way rely on the assumption that specific distances between verbal anchors placed on the scale exist and that relationships between verbal anchors from different dimensions that are assessed (e.g. thermal sensation and comfort) do not change. Another inherent assumption is that such scales are independent of the context in which they are used (climate zone, season, etc.). Despite their use worldwide, there is indication that contextual differences influence the way the scales are perceived and therefore question the reliability of the scales’ interpretation. To address this issue, a large international collaborative questionnaire study was conducted in 26 countries, using 21 different languages, which led to a dataset of 8225 questionnaires. Results, analysed by means of robust statistical techniques, revealed that only a subset of the responses are in accordance with the mentioned assumptions. Significant differences appeared between groups of participants in their perception of the scales, both in relation to distances of the anchors and relationships between scales. It was also found that respondents’ interpretations of scales changed with contextual factors, such as climate, season, and language. These findings highlight the need to carefully consider context-dependent factors in interpreting and reporting results from thermal comfort studies or post-occupancy evaluations, as well as to revisit the use of rating scales and the analysis methods used in thermal comfort studies to improve their reliability.
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| 18. |
- Shipilin, Mikhail, et al.
(författare)
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In Situ Surface-Sensitive Investigation of Multiple Carbon Phases on Fe(110) in the Fischer-Tropsch Synthesis
- 2022
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Ingår i: ACS Catalysis. - : American Chemical Society (ACS). - 2155-5435. ; 12:13, s. 7609-7621
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Tidskriftsartikel (refereegranskat)abstract
- Carbide formation on iron-based catalysts is an integral and, arguably, the most important part of the Fischer–Tropsch synthesis process, converting CO and H2 into synthetic fuels and numerous valuable chemicals. Here, we report an in situ surface-sensitive study of the effect of pressure, temperature, time, and gas feed composition on the growth dynamics of two distinct iron–carbon phases with the octahedral and trigonal prismatic coordination of carbon sites on an Fe(110) single crystal acting as a model catalyst. Using a combination of state-of-the-art X-ray photoelectron spectroscopy at an unprecedentedly high pressure, high-energy surface X-ray diffraction, mass spectrometry, and theoretical calculations, we reveal the details of iron surface carburization and product formation under semirealistic conditions. We provide a detailed insight into the state of the catalyst’s surface in relation to the reaction.
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| 19. |
- Winkelmann, Iven, 1989-, et al.
(författare)
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Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing
- 2022
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The strict exchange of protons for sodium ions across cell membranes by Na+/H+ exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na+/H+ exchange can be modelled as competition between H+ and Na+ to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na+/H+ antiporter NhaA from Escherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 angstrom. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na+ to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter.
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