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  • 1. Agerberth, B
    et al.
    Gunne, H
    Odeberg, Jacob
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Kogner, P
    Boman, H G
    Gudmundsson, G H
    FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis.1995Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 92, nr 1, s. 195-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PR-39, a proline/arginine-rich peptide antibiotic, has been purified from pig intestine and later shown to originate in the bone marrow. Intending to isolate a clone for a human counterpart to PR-39, we synthesized a PCR probe derived from the PR-39 gene. However, when this probe was used to screen a human bone marrow cDNA library, eight clones were obtained with information for another putative human peptide antibiotic, designated FALL-39 after the first four residues. FALL-39 is a 39-residue peptide lacking cysteine and tryptophan. All human peptide antibiotics previously isolated (or predicted) belong to the defensin family and contain three disulfide bridges. The clone for prepro-FALL-39 encodes a cathelin-like precursor protein with 170 amino acid residues. We have postulated a dibasic processing site for the mature FALL-39 and chemically synthesized the putative peptide. In basal medium E, synthetic FALL-39 was highly active against Escherichia coli and Bacillus megaterium. Residues 13-34 in FALL-39 can be predicted to form a perfect amphiphatic helix, and CD spectra showed that medium E induced 30% helix formation in FALL-39. RNA blot analyses disclosed that the gene for FALL-39 is expressed mainly in human bone marrow and testis.

  • 2. Aizman, O.
    et al.
    Uhlen, P.
    Lal, M.
    Brismar, Hjalmar
    Aperia, A.
    Ouabain, a steroid hormone that signals with slow calcium oscillations2001Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 98, nr 23, s. 13420-13424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The plant-derived steroid, digoxin, a specific inhibitor of Na,K-ATPase, has been used for centuries in the treatment of heart disease. Recent studies demonstrate the presence of a digoxin analog, ouabain, in mammalian tissue, but its biological role has not been elucidated. Here, we show in renal epithelial cells that ouabain, in doses causing only partial Na,K-ATPase inhibition, acts as a biological inducer of regular, low-frequency intracellular calcium ([Ca2+](i)) oscillations that elicit activation of the transcription factor, NF-KB. Partial inhibition of Na,K-ATPase using low extracellular K+ and depolarization of cells did not have these effects. Incubation of cells in Ca2+-free media, inhibition of voltage-gated calcium channels, inositol triphosphate receptor antagonism, and redistribution of actin to a thick layer adjacent to the plasma membrane abolished [Ca2+](i) oscillations, indicating that they were caused by a concerted action of inositol triphosphate receptors and capacitative calcium entry via plasma membrane channels. Blockade of ouabain-induced [C-a2+](i) oscillations prevented activation of NF-kappaB. The results demonstrate a new mechanism for steroid signaling via plasma membrane receptors and underline a novel role for the steroid hormone, ouabain, as a physiological inducer of [Ca2+](i) oscillations involved in transcriptional regulation in mammalian cells.

  • 3. Alava, Mikko
    et al.
    Ardelius, John
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Aurell, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Kaski, P.
    Krishnamurthy, S.
    Orponen, P.
    Seitz, S
    Circumspect descent prevails in solving random constraint satisfaction problems2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 40, s. 15253-15257Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We study the performance of stochastic local search algorithms for random instances of the K-satisfiability (K-SAT) problem. We present a stochastic local search algorithm, ChainSAT, which moves in the energy landscape of a problem instance by never going upwards in energy. ChainSAT is a focused algorithm in the sense that it focuses on variables occurring in unsatisfied clauses. We show by extensive numerical investigations that ChainSAT and other focused algorithms solve large K-SAT instances almost surely in linear time, up to high clause-to-variable ratios a; for example, for K = 4 we observe linear-time performance well beyond the recently postulated clustering and condensation transitions in the solution space. The performance of ChainSAT is a surprise given that by design the algorithm gets trapped into the first local energy minimum it encounters, yet no such minima are encountered. We also study the geometry of the solution space as accessed by stochastic local search algorithms.

  • 4. Alkasalias, Twana
    et al.
    Alexeyenko, Andrey
    Hennig, Katharina
    Danielsson, Frida
    Lebbink, Robert Jan
    Fielden, Matthew
    Turunen, S. Pauliina
    Lehti, Kaisa
    Kashuba, Vladimir
    Madapura, Harsha S.
    Bozoky, Benedek
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Balland, Martial
    Guven, Hayrettin
    Klein, George
    Gad, Annica K. B.
    Pavlova, Tatiana
    RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 8, s. E1413-E1421Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins over-expressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of a-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

  • 5. Ambikan, Anoop T.
    et al.
    Elaldi, Nazif
    Svensson-Akusjärvi, Sara
    Bagci, Binnur
    Pektas, Ayse Nur
    Hewson, Roger
    United Kingdom Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom.
    Bagci, Gokhan
    Arasli, Mehmet
    Appelberg, Sofia
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Sood, Vikas
    Végvári, Ákos
    Benfeitas, Rui
    Gupta, Soham
    Cetin, Ilhan
    Mirazimi, Ali
    Neogi, Ujjwal
    Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection2023Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, nr 37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.

  • 6. Ambort, D.
    et al.
    Johansson, M.E.V.
    Gustafsson, J. K.
    Nilsson, Harriet
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Medicinteknik och hälsosystem, Strukturell bioteknik. Department of Biosciences and Nutrition, Karolinska Institutet.
    Ermund, A.
    Johansson, B.R.
    Koeck, Philip J. B.
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik. Department of Biosciences and Nutrition, Karolinska Institutet.
    Hebert, Hans
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik. Department of Biosciences and Nutrition, Karolinska Institutet.
    Hansson, G.C.
    Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 15, s. 5645-5650Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca2+ it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. TheMUC2-N aggregates were dissolved by removing Ca2+ and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.

  • 7.
    Andersson, David A.
    et al.
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Simak, Sergei I.
    Skorodumova, Natalia V.
    Abrikosov, Igor A.
    Johansson, Börje
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Optimization of ionic conductivity in doped ceria2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 10, s. 3518-3521Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oxides with the cubic fluorite structure, e.g., ceria (CeO2), are known to be good solid electrolytes when they are doped with cations of lower valence than the host cations. The high ionic conductivity of doped ceria makes it an attractive electrolyte for solid oxide fuel cells, whose prospects as an environmentally friendly power source are very promising. In these electrolytes, the current is carried by oxygen ions that are transported by oxygen vacancies, present to compensate for the lower charge of the dopant cations. Ionic conductivity in ceria is closely related to oxygen-vacancy formation and migration properties. A clear physical picture of the connection between the choice of a dopant and the improvement of ionic conductivity in ceria is still lacking. Here we present a quantum-mechanical first-principles study of the influence of different trivalent impurities on these properties. Our results reveal a remarkable correspondence between vacancy properties at the atomic level and the macroscopic ionic conductivity. The key parameters comprise migration barriers for bulk diffusion and vacancy-dopant interactions, represented by association (binding) energies of vacancy-dopant clusters. The interactions can be divided into repulsive elastic and attractive electronic parts. In the optimal electrolyte, these parts should balance. This finding offers a simple and clear way to narrow the search for superior dopants and combinations of dopants. The ideal dopant should have an effective atomic number between 61 (Pm) and 62 (Sm), and we elaborate that combinations of Nd/Sm and Pr/Gd show enhanced ionic conductivity, as compared with that for each element separately.

  • 8. Arapan, S.
    et al.
    Mao, H.
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Prediction of incommensurate crystal structure in Ca at high pressure2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 52, s. 20627-20630Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ca shows an interesting high-pressure phase transformation sequence, but, despite similar physical properties at high pressure and affinity in the electronic structure with its neighbors in the periodic table, no complex phase has been identified for Ca so far. We predict an incommensurate high-pressure phase of Ca from first principle calculations and describe a procedure of estimating incommensurate structure parameters by means of electronic structure calculations for periodic crystals. Thus, by using the ab initio technique for periodic structures, one can get not only reliable information about the electronic structure and structural parameters of an incommensurate phase, but also identify and predict such phases in new elements.

  • 9. Attems, Johannes
    et al.
    Alpar, Alan
    Spence, Lauren
    McParland, Shane
    Heikenwalder, Mathias
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Tanila, Heikki
    Hökfelt, Tomas G. M.
    Harkany, Tibor
    Clusters of secretagogin-expressing neurons in the aged human olfactory tract lack terminal differentiation2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 16, s. 6259-6264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Expanding the repertoire of molecularly diverse neurons in the human nervous system is paramount to characterizing the neuronal networks that underpin sensory processing. Defining neuronal identities is particularly timely in the human olfactory system, whose structural differences from nonprimate macrosmatic species have recently gained momentum. Here, we identify clusters of bipolar neurons in a previously unknown outer "shell" domain of the human olfactory tract, which express secretagogin, a cytosolic Ca2+ binding protein. These "shell" neurons are wired into the olfactory circuitry because they can receive mixed synaptic inputs. Unexpectedly, secretagogin is often coexpressed with polysialylated-neural cell adhesion molecule, beta-III-tubulin, and calretinin, suggesting that these neurons represent a cell pool that might have escaped terminal differentiation into the olfactory circuitry. We hypothesized that secretagogin-containing "shell" cells may be eliminated from the olfactory axis under neurodegenerative conditions. Indeed, the density, but not the morphological or neurochemical integrity, of secretagogin-positive neurons selectively decreases in the olfactory tract in Alzheimer's disease. In conclusion, secretagogin identifies a previously undescribed cell pool whose cytoarchitectonic arrangements and synaptic connectivity are poised to modulate olfactory processing in humans.

  • 10.
    Ayoglu, Burcu
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Mitsios, Nicholas
    Kockum, Ingrid
    Khademi, Mohsen
    Zandian, Arash
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sjoberg, Ronald
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Forsstrom, Bjorn
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bredenberg, Johan
    Bomfim, Izaura Lima
    Holmgren, Erik
    Gronlund, Hans
    Guerreiro-Cacais, Andre Ortlieb
    Abdelmagid, Nada
    Uhlen, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Waterboer, Tim
    Alfredsson, Lars
    Mulder, Jan
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Olsson, Tomas
    Nilsson, Peter
    Anoctamin 2 identified as an autoimmune target in multiple sclerosis2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 8, s. 2188-2193Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

  • 11.
    Bakan, Andrew
    et al.
    Natl Acad Sci Ukraine, Inst Math, UA-01601 Kiev, Ukraine..
    Hedenmalm, Håkan
    KTH, Skolan för teknikvetenskap (SCI), Matematik (Inst.), Matematik (Avd.).
    Montes-Rodriguez, Alfonso
    Univ Seville, Dept Math Anal, ES-41004 Seville, Spain..
    Radchenko, Danylo
    Swiss Fed Inst Technol Zurich ETHZ, Dept Math, CH-8092 Zurich, Switzerland..
    Viazovska, Maryna
    Swiss Fed Inst Technol Lausanne EPFL, Inst Math, CH-1015 Lausanne, Switzerland..
    Fourier uniqueness in even dimensions2021Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, nr 15, artikel-id e2023227118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In recent work, methods from the theory of modular forms were used to obtain Fourier uniqueness results in several key dimensions (d = 1, 8, 24), in which a function could be uniquely reconstructed from the values of it and its Fourier transform on a discrete set, with the striking application of resolving the sphere packing problem in dimensions d = 8 and d = 24. In this short note, we present an alternative approach to such results, viable in even dimensions, based instead on the uniqueness theory for the KleinGordon equation. Since the existing method for the Klein-Gordon uniqueness theory is based on the study of iterations of Gauss-type maps, this suggests a connection between the latter and methods involving modular forms. The derivation of Fourier uniqueness from the Klein-Gordon theory supplies conditions on the given test function for Fourier interpolation, which are hoped to be optimal or close to optimal.

  • 12.
    Baym, Gordon
    et al.
    Univ Illinois, Dept Phys, Urbana, IL 61801 USA..
    Pethick, Christopher
    KTH, Centra, Nordic Institute for Theoretical Physics NORDITA. Univ Copenhagen, Niels Bohr Int Acad, Niels Bohr Inst, DK-2100 Copenhagen O, Denmark.;Stockholm Univ, SE-10691 Stockholm, Sweden..
    Ben Mottelson: Codeveloper of the unified theory of the structure and dynamics of atomic nuclei2022Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, nr 40, artikel-id e2214052119Artikel i tidskrift (Övrigt vetenskapligt)
  • 13.
    Bernsel, Andreas
    et al.
    Stockholm University.
    Viklund, Håkan
    Stockholm University.
    Falk, Jenny
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    von Heijne, Gunnar
    Stockholm University.
    Elofsson, Arne
    Stockholm University.
    Prediction of membrane-protein topology from first principles2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 20, s. 7177-7781Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The current best membrane-protein topology-prediction methods are typically based on sequence statistics and contain hundreds of parameters that are optimized on known topologies of membrane proteins. However, because the insertion of transmembrane helices into the membrane is the outcome of molecular interactions among protein, lipids and water, it should be possible to predict topology by methods based directly on physical data, as proposed >20 years ago by Kyte and Doolittle. Here, we present two simple topology-prediction methods using a recently published experimental scale of position-specific amino acid contributions to the free energy of membrane insertion that perform on a par with the current best statistics-based topology predictors. This result suggests that prediction of membrane-protein topology and structure directly from first principles is an attainable goal, given the recently improved understanding of peptide recognition by the translocon.

  • 14.
    Bidkhori, Gholamreza
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Klevstig, Martina
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is one of the most frequent forms of liver cancer, and effective treatment methods are limited due to tumor heterogeneity. There is a great need for comprehensive approaches to stratify HCC patients, gain biological insights into subtypes, and ultimately identify effective therapeutic targets. We stratified HCC patients and characterized each subtype using transcriptomics data, genome-scale metabolic networks and network topology/controllability analysis. This comprehensive systems-level analysis identified three distinct subtypes with substantial differences in metabolic and signaling pathways reflecting at genomic, transcriptomic, and proteomic levels. These subtypes showed large differences in clinical survival associated with altered kynurenine metabolism, WNT/beta-catenin-associated lipid metabolism, and PI3K/AKT/mTOR signaling. Integrative analyses indicated that the three subtypes rely on alternative enzymes (e.g., ACSS1/ACSS2/ACSS3, PKM/PKLR, ALDOB/ALDOA, MTHFD1L/MTHFD2/MTHFD1) to catalyze the same reactions. Based on systems-level analysis, we identified 8 to 28 subtype-specific genes with pivotal roles in controlling the metabolic network and predicted that these genes may be targeted for development of treatment strategies for HCC subtypes by performing in silico analysis. To validate our predictions, we performed experiments using HepG2 cells under normoxic and hypoxic conditions and observed opposite expression patterns between genes expressed in high/moderate/low-survival tumor groups in response to hypoxia, reflecting activated hypoxic behavior in patients with poor survival. In conclusion, our analyses showed that the heterogeneous HCC tumors can be stratified using a metabolic network-driven approach, which may also be applied to other cancer types, and this stratification may have clinical implications to drive the development of precision medicine.

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  • 15. Blomqvist, A.
    et al.
    Araujo, C. M.
    Srepusharawoot, P.
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Li-decorated metal-organic framework 5: A route to achieving a suitable hydrogen storage medium2007Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, nr 51, s. 20173-20176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A significant improvement in molecular hydrogen uptake properties is revealed by our ab initio calculations for Li-decorated metal-organic framework 5. We have found that two Li atoms are strongly adsorbed on the surfaces of the six-carbon rings, one on each side, carrying a charge of +0.9e per Li atom. Each Li can cluster three H-2 molecules around itself with a binding energy of 12 kJ (mol H-2)(-1). Furthermore, we show from ab initio molecular dynamics simulations with a hydrogen loading of 18 H2 per formula unit that a hydrogen uptake of 2.9 wt % at 200 K and 2.0 wt % at 300 K is achievable. To our knowledge, this is the highest hydrogen storage capacity reported for metal-organic framework 5 under such thermodynamic conditions.

  • 16.
    Brusini, Irene
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Medicinteknik och hälsosystem, Medicinsk avbildning.
    Carneiro, Miguel
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal.;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal..
    Wang, Chunliang
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Medicinteknik och hälsosystem, Medicinsk avbildning.
    Rubin, Carl-Johan
    Uppsala Univ, Sci Life Lab Uppsala, Dept Med Biochem & Microbiol, S-75236 Uppsala, Sweden..
    Ring, Henrik
    Uppsala Univ, Dept Neurosci, S-75236 Uppsala, Sweden..
    Afonso, Sandra
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal..
    Blanco-Aguiar, Jose A.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal.;CSIC, Inst Invest Recursos Cineget IREC, Ciudad Real 13005, Spain.;UCLM, CSIC, Ciudad Real 13005, Spain..
    Ferrand, Nuno
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal.;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.;Univ Johannesburg, Dept Zool, ZA-2006 Auckland Pk, South Africa..
    Rafati, Nima
    Uppsala Univ, Sci Life Lab Uppsala, Dept Med Biochem & Microbiol, S-75236 Uppsala, Sweden..
    Villafuerte, Rafael
    CSIC, IESA, Cordoba 14004, Spain..
    Smedby, Örjan
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Medicinteknik och hälsosystem, Medicinsk avbildning.
    Damberg, Peter
    Karolinska Univ Hosp, Karolinska Expt Res & Imaging Ctr, S-17176 Solna, Sweden..
    Hallbook, Finn
    Uppsala Univ, Dept Neurosci, S-75236 Uppsala, Sweden..
    Fredrikson, Mats
    Uppsala Univ, Dept Psychol, S-75236 Uppsala, Sweden.;Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden..
    Andersson, Leif
    Uppsala Univ, Sci Life Lab Uppsala, Dept Med Biochem & Microbiol, S-75236 Uppsala, Sweden.;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.;Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Changes in brain architecture are consistent with altered fear processing in domestic rabbits2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 28, s. 7380-7385Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.

  • 17.
    Caceres, Rodrigo
    et al.
    PSL Res Univ, CNRS, Lab Physicochim Curie, Inst Curie, F-75005 Paris, France.;Univ Paris 05, F-75005 Paris, France.;Sorbonne Univ, F-75005 Paris, France..
    Bojanala, Nagagireesh
    PSL Res Univ, CNRS, Lab Physicochim Curie, Inst Curie, F-75005 Paris, France.;Sorbonne Univ, F-75005 Paris, France..
    Kelley, Laura C.
    Duke Univ, Dept Biol, Regenerat Next, Durham, NC 27705 USA..
    Dreier, Jes
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Manzi, John
    PSL Res Univ, CNRS, Lab Physicochim Curie, Inst Curie, F-75005 Paris, France.;Sorbonne Univ, F-75005 Paris, France..
    Di Federico, Fahima
    PSL Res Univ, CNRS, Lab Physicochim Curie, Inst Curie, F-75005 Paris, France.;Sorbonne Univ, F-75005 Paris, France..
    Chi, Qiuyi
    Duke Univ, Dept Biol, Regenerat Next, Durham, NC 27705 USA..
    Risler, Thomas
    PSL Res Univ, CNRS, Lab Physicochim Curie, Inst Curie, F-75005 Paris, France.;Sorbonne Univ, F-75005 Paris, France..
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sherwood, David R.
    Duke Univ, Dept Biol, Regenerat Next, Durham, NC 27705 USA..
    Plastino, Julie
    PSL Res Univ, CNRS, Lab Physicochim Curie, Inst Curie, F-75005 Paris, France.;Sorbonne Univ, F-75005 Paris, France..
    Forces drive basement membrane invasion in Caenorhabditis elegans2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 45, s. 11537-11542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During invasion, cells breach basement membrane (BM) barriers with actin-rich protrusions. It remains unclear, however, whether actin polymerization applies pushing forces to help break through BM, or whether actin filaments play a passive role as scaffolding for targeting invasive machinery. Here, using the developmental event of anchor cell (AC) invasion in Caenorhabditis elegans, we observe that the AC deforms the BM and underlying tissue just before invasion, exerting forces in the tens of nanonewtons range. Deformation is driven by actin polymerization nucleated by the Arp2/3 complex and its activators, whereas formins and cross-inkers are dispensable. Delays in invasion upon actin regulator loss are not caused by defects in AC polarity, trafficking, or secretion, as appropriate markers are correctly localized in the AC even when actin is reduced and invasion is disrupted. Overall force production emerges from this study as one of the main tools that invading cells use to promote BM disruption in C. elegans.

  • 18.
    Caminata, Alessio
    et al.
    Univ Genoa, Dipartimento Matemat, I-16146 Genoa, Italy..
    Giansiracusa, Noah
    Bentley Univ, Dept Math Sci, Waltham, MA 02452 USA..
    Moon, Han-Bom
    Fordham Univ, Dept Math, New York, NY 10023 USA..
    Schaffler, Luca
    KTH, Skolan för teknikvetenskap (SCI), Matematik (Inst.).
    Point configurations, phylogenetic trees, and dissimilarity vectors2021Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, nr 12, artikel-id e2021244118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In 2004, Pachter and Speyer introduced the higher dissimilarity maps for phylogenetic trees and asked two important questions about their relation to the tropical Grassmannian. Multiple authors, using independent methods, answered affirmatively the first of these questions, showing that dissimilarity vectors lie on the tropical Grassmannian, but the second question, whether the set of dissimilarity vectors forms a tropical subvariety, remained opened. We resolve this question by showing that the tropical balancing condition fails. However, by replacing the definition of the dissimilarity map with a weighted variant, we show that weighted dissimilarity vectors form a tropical subvariety of the tropical Grassmannian in exactly the way that Pachter and Speyer envisioned. Moreover, we provide a geometric interpretation in terms of configurations of points on rational normal curves and construct a finite tropical basis that yields an explicit characterization of weighted dissimilarity vectors.

  • 19. Caravaca, A. S.
    et al.
    Gallina, A. L.
    Tarnawski, L.
    Shavva, V. S.
    Colas, R. A.
    Dalli, J.
    Malin, S. G.
    Hult, Henrik
    KTH, Skolan för teknikvetenskap (SCI), Matematik (Inst.).
    Arnardottir, H.
    Olofsson, P. S.
    Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit2022Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, nr 22, artikel-id e2023285119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR. 

  • 20.
    Ceolin, Denis
    et al.
    Synchrotron SOLEIL, F-91191 Gif Sur Yvette, France..
    Liu, Ji-Cai
    North China Elect Power Univ, Dept Math & Phys, Beijing 102206, Peoples R China..
    da Cruz, Vinicius Vaz
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Teoretisk kemi och biologi.
    Ågren, Hans
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Teoretisk kemi och biologi. Uppsala Univ, Dept Phys & Astron, S-75120 Uppsala, Sweden..
    Journel, Loic
    Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France..
    Guillemin, Renaud
    Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France..
    Marchenko, Tatiana
    Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France..
    Kushawaha, Rajesh K.
    Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France..
    Piancastelli, Maria Novella
    Uppsala Univ, Dept Phys & Astron, S-75120 Uppsala, Sweden.;Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France..
    Puettner, Ralph
    Free Univ Berlin, Fachbereich Phys, D-14195 Berlin, Germany..
    Simon, Marc
    Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France..
    Gel'mukhanov, Faris
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Teoretisk kemi och biologi. Synchrotron SOLEIL, F-91191 Gif Sur Yvette, France.;Siberian Fed Univ, Inst Nanotechnol Spect & Quantum Chem, Krasnoyarsk 660041, Russia..
    Recoil-induced ultrafast molecular rotation probed by dynamical rotational Doppler effect2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 11, s. 4877-4882Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Observing and controlling molecular motion and in particular rotation are fundamental topics in physics and chemistry. To initiate ultrafast rotation, one needs a way to transfer a large angular momentum to the molecule. As a showcase, this was performed by hard X-ray C1s ionization of carbon monoxide accompanied by spinning up the molecule via the recoil "kick" of the emitted fast photoelectron. To visualize this molecular motion, we use the dynamical rotational Doppler effect and an X-ray "pump-probe" device offered by nature itself: the recoil-induced ultrafast rotation is probed by subsequent Auger electron emission. The time information in our experiment originates from the natural delay between the C1s photoionization initiating the rotation and the ejection of the Auger electron. From a more general point of view, time-resolved measurements can be performed in two ways: either to vary the "delay" time as in conventional time-resolved pump-probe spectroscopy and use the dynamics given by the system, or to keep constant delay time and manipulate the dynamics. Since in our experiment we cannot change the delay time given by the core-hole lifetime tau, we use the second option and control the rotational speed by changing the kinetic energy of the photoelectron. The recoil-induced rotational dynamics controlled in such a way is observed as a photon energy-dependent asymmetry of the Auger line shape, in full agreement with theory. This asymmetry is explained by a significant change of the molecular orientation during the core-hole lifetime, which is comparable with the rotational period.

  • 21.
    Chandok, Meena, R.
    et al.
    BTI, Cornell University, USA.
    Ekengren, Sophia K.
    BTI, Cornell University, USA.
    Martin, Gregory, B.
    BTI, Cornell University.
    Klessig, Daniel, F.
    BTI, Cornell University, USA.
    Individual Suppression of pathogen-inducible NO synthase (iNOS) activity in tomato increases susceptibility to Pseudomonas syringae2004Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, s. 8239-8244Artikel i tidskrift (Refereegranskat)
  • 22.
    Chang, Weipang
    et al.
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Pedroni, Andrea
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Hohendorf, Victoria
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Giacomello, Stefania
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hibi, Masahiko
    Nagoya Univ, Grad Sch Sci, Div Biol Sci, Nagoya, Aichi 4648602, Japan..
    Koester, Reinhard W.
    Tech Univ Carolo Wilhelmina Braunschweig, Zool Inst, Cellular & Mol Neurobiol, D-38106 Braunschweig, Germany..
    Ampatzis, Konstantinos
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Functionally distinct Purkinje cell types show temporal precision in encoding locomotion2020Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, nr 29, s. 17330-17337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purkinje cells, the principal neurons of cerebellar computations, are believed to comprise a uniform neuronal population of cells, each with similar functional properties. Here, we show an undiscovered heterogeneity of adult zebrafish Purkinje cells, revealing the existence of anatomically and functionally distinct cell types. Dual patch-clamp recordings showed that the cerebellar circuit contains all Purkinje cell types that cross-communicate extensively using chemical and electrical synapses. Further activation of spinal central pattern generators (CPGs) revealed unique phase-locked activity from each Purkinje cell type during the locomotor cycle. Thus, we show intricately organized Purkinje cell networks in the adult zebrafish cerebellum that encode the locomotion rhythm differentially, and we suggest that these organizational properties may also apply to other cerebellar functions.

  • 23.
    Chen, Xinsong
    et al.
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden.
    Sifakis, Emmanouil G.
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden.
    Robertson, Stephanie
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden; Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm 17176, Sweden.
    Neo, Shi Yong
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden.
    Jun, Seong-Hwan
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Datavetenskap, Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Tong, Le
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden.
    Min, Apple Tay Hui
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
    Lövrot, John
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden.
    Hellgren, Roxanna
    Department of Breast Imaging, Södersjukhuset, Stockholm 11828, Sweden.
    Margolin, Sara
    Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm 11883, Sweden.
    Bergh, Jonas
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden; Breast Center, Theme Cancer, Karolinska University Hospital, Stockholm 17176, Sweden.
    Foukakis, Theodoros
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden; Breast Center, Theme Cancer, Karolinska University Hospital, Stockholm 17176, Sweden.
    Lagergren, Jens
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Datavetenskap, Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Computational Biology, Royal Institute of Technology, Science for Life Laboratory, Stockholm 17165, Sweden.
    Lundqvist, Andreas
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden.
    Ma, Ran
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden.
    Hartman, Johan
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17164, Sweden; Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm 17176, Sweden.
    Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction2023Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, nr 1, artikel-id e2209856120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with different genetic features and pathological characteristics. Although a large number of antineoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed, highlighting the need for efficient treatment prediction for individualized therapy. Several patient-derived models have been established lately for the prediction of drug response. However, each of these models has its limitations that impede their clinical application. Here, we report that the whole-tumor cell culture (WTC) ex vivo model could be stably established from all breast tumors with a high success rate (98 out of 116), and it could reassemble the parental tumors with the endogenous microenvironment. We observed strong clinical associations and predictive values from the investigation of a broad range of BC therapies with WTCs derived from a patient cohort. The accuracy was further supported by the correlation between WTC-based test results and patients' clinical responses in a separate validation study, where the neoadjuvant treatment regimens of 15 BC patients were mimicked. Collectively, the WTC model allows us to accomplish personalized drug testing within 10 d, even for small-sized tumors, highlighting its potential for individualized BC therapy. Furthermore, coupled with genomic and transcriptomic analyses, WTC-based testing can also help to stratify specific patient groups for assignment into appropriate clinical trials, as well as validate potential biomarkers during drug development.

  • 24. Clatot, Jerome
    et al.
    Currin, Christopher B.
    Liang, Qiansheng
    Pipatpolkai, Tanadet
    Massey, Shavonne L.
    Helbig, Ingo
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Vogels, Tim P.
    Covarrubias, Manuel
    Goldberg, Ethan M.
    A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction2024Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 121, nr 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.

  • 25.
    Danielsson, Frida
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Skogs, Marie
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Huss, Mikael
    Rexhepaj, Elton
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    O'Hurley, Gillian
    Klevebring, Daniel
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Gad, Annica K. B.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 17, s. 6853-6858Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a four-stage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that similar to 6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.

  • 26.
    Deguchi, Shigeru
    et al.
    Institute of Biogeosciences, Japan Agency for Marine-Earth Science and Technology, Yokosuka 237-0061, Japan.
    Shimoshige, Hirokazu
    Institute of Biogeosciences, Japan Agency for Marine-Earth Science and Technology, Yokosuka 237-0061, Japan.
    Tsudome, Mikiko
    Institute of Biogeosciences, Japan Agency for Marine-Earth Science and Technology, Yokosuka 237-0061, Japan.
    Mukai, Sada-atsu
    Institute of Biogeosciences, Japan Agency for Marine-Earth Science and Technology, Yokosuka 237-0061, Japan.
    Corkery, Robert W.
    YKI, Institute for Surface Chemistry, Stockholm, Sweden.
    Ito, Susumu
    Department of Bioscience and Biotechnology, Faculty of Agriculture, University of the Ryukyus, Nishihra, Okinawa 903-0213, Japan.
    Horikoshi, Koki
    Institute of Biogeosciences, Japan Agency for Marine-Earth Science and Technology, Yokosuka 237-0061, Japan.
    Microbial growth at hyperaccelerations up to 403,627 x g2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 19, s. 7997-8002Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is well known that prokaryotic life can withstand extremes of temperature, pH, pressure, and radiation. Little is known about the proliferation of prokaryotic life under conditions of hyperacceleration attributable to extreme gravity, however. We found that living organisms can be surprisingly proliferative during hyperacceleration. In tests reported here, a variety of microorganisms, including Gram-negative Escherichia coli, Paracoccus denitrificans, and Shewanella amazonensis; Gram-positive Lactobacillus delbrueckii; and eukaryotic Saccharomyces cerevisiae, were cultured while being subjected to hyperaccelerative conditions. We observed and quantified robust cellular growth in these cultures across a wide range of hyperacceleration values. Most notably, the organisms P. denitrificans and E. coli were able to proliferate even at 403,627 × g. Analysis shows that the small size of prokaryotic cells is essential for their proliferation under conditions of hyperacceleration. Our results indicate that microorganisms cannot only survive during hyperacceleration but can display such robust proliferative behavior that the habitability of extraterrestrial environments must not be limited by gravity.

  • 27. Delios, A.
    et al.
    Clemente, E. G.
    Wu, T.
    Tan, H.
    Wang, Y.
    Gordon, M.
    Viganola, D.
    Chen, Z.
    Dreber, A.
    Johannesson, M.
    Pfeiffer, T.
    Uhlmann, E. L.
    Al-Aziz, A. M. A.
    Abraham, A. T.
    Trojan, J.
    Adamkovic, M.
    Agadullina, E.
    Ahn, J.
    Akinci, C.
    Akkas, H.
    Albrecht, D.
    Alzahawi, S.
    Amaral-Baptista, M.
    Anand, R.
    Ang, K. F. U.
    Anseel, F.
    Aruta, J. J. B. R.
    Ashraf, M.
    Baker, B. J.
    Bao, X.
    Baskin, E.
    Bathula, H.
    Bauman, C. W.
    Bavolar, J.
    Bayraktar, S.
    Beckman, S. E.
    Benjamin, A. S.
    Brown, S. E. V.
    Buckley, Jeffrey
    KTH, Skolan för industriell teknik och management (ITM), Lärande.
    Buitrago, R. E.
    Bution, J. L.
    Byrd, N.
    Carrera, C.
    Caruso, E. M.
    Chen, M.
    Chen, L.
    Cicerali, E. E.
    Cohen, E. D.
    Crede, M.
    Cummins, J.
    Dahlander, L.
    Daniels, D. P.
    Daskalo, L. L.
    Dawson, I. G. J.
    Day, M. V.
    Dietl, E.
    Domurat, A.
    Dsilva, J.
    Du Plessis, C.
    Dubrov, D. I.
    Edris, S.
    Elbaek, C. T.
    Elsherif, M. M.
    Evans, T. R.
    Fellenz, M. R.
    Fiedler, S.
    Firat, M.
    Freitag, R.
    Furrer, R. A.
    Gautam, R.
    Gautam, D. K.
    Gearin, B.
    Gerschewski, S.
    Ghasemi, O.
    Ghasemi, Z.
    Ghosh, A.
    Giani, C.
    Goldberg, M. H.
    Goswami, M.
    Graf-Vlachy, L.
    Rajeshwari, H.
    Griffith, J. A.
    Grigoryev, D.
    Gu, J.
    Hadida, A. L.
    Hafenbrack, A. C.
    Hafenbrädl, S.
    Hammersley, J. J.
    Han, H.
    Harman, J. L.
    Hartanto, A.
    Henkel, A. P.
    Ho, Y. -C
    Holding, B. C.
    Holzmeister, F.
    Horobet, A.
    Huang, T. S. -T
    Huang, Y.
    Huntsinger, J. R.
    Idzikowska, K.
    Imada, H.
    Imran, R.
    Ingels, M. J.
    Jaeger, B.
    Janssen, S. M. J.
    Jia, F.
    Jiménez, A.
    Jin, J. L.
    Johannes, N.
    Jolles, D.
    Jozefiakova, B.
    Kačmár, P.
    Kalandadze, T.
    Kalimeri, K.
    Kang, P.
    Kantorowicz, J.
    Karada, D.
    Karimi-Rouzbahani, H.
    Kee, D. M. H.
    Keller, L.
    Khan, H. A.
    Knutsson, M.
    Kombeiz, O.
    Korniychuk, A.
    Kowal, M.
    Leder, J.
    Liang, L. W.
    Liew, T.
    Lin, F.
    Liu, C.
    Liu, B.
    Longo, M. C.
    Lovakov, A.
    Low, M. P.
    Lucas, G. J. M.
    Lukason, O.
    Ly, A. L.
    Ma, Z.
    Mafael, A.
    Mahmoudkalayeh, S.
    Manheim, D.
    Marcus, A.
    Marsh, M. S.
    Martin, J. M.
    Martinez, L. E.
    Martinoli, M.
    Martončik, M.
    Masters-Waage, T. C.
    Mata, R.
    Mazloomi, H.
    Mccarthy, R. J.
    Millroth, P.
    Mishra, M.
    Mishra, S.
    Mohr, A.
    Moreau, D.
    Myer, A.
    Nadler, A.
    Nair, S.
    Nilsonne, G.
    Niszczota, P.
    O'Mahony, A.
    Oberhauser, M.
    Obloj, T.
    Orhan, M. A.
    Oswald, F.
    Otterbring, T.
    Otto, P. E.
    Padrón-Hernández, I.
    Pan, A. J.
    Paruzel-Czachura, M.
    Pfuhl, G.
    Pirrone, A.
    Porcher, S.
    Protzko, J.
    Qi, S.
    Rahal, R. -M
    Rahman, Md.S.
    Reina, M. L.
    Rentala, S.
    Riaz, Z.
    Ropovik, I.
    Röseler, L.
    Ross, R. M.
    Rotella, A.
    Roth, L. H. O.
    Roulet, T. J.
    Rubin, M. M.
    Sammartino, A.
    Sanchez, J.
    Saville, A. D.
    Schaerer, M.
    Schleu, J. E.
    Schmallenbach, L.
    Schnabel, L.
    Spüntrup, F. S.
    Schumpe, B. M.
    Senanayake, T.
    Seri, R.
    Sheng, F.
    Snider, R. E.
    Song, D.
    Song, V.
    Starnawska, S. E.
    Stern, K. A.
    Stevens, S. M.
    Strømland, E.
    Su, W.
    Sun, H.
    Sweeney, K. P.
    Takamatsu, R.
    Terskova, M.
    Tey, K. S.
    Tierney, W.
    Todorova, M. M.
    Tolstoy, D.
    Torkkeli, L.
    Tybur, J. M.
    Valderrey, F. J.
    Vallina-Hernandez, A. M.
    Vasudevan, R. P.
    Rao, G. V.
    Vernet, A.
    Vissak, T.
    Voss, H.
    Wahle, T.
    Wai, J.
    Wakabayashi, L. E. T.
    Wang, J.
    Wang, P.
    Warmenhoven, R. W.
    Wennberg, K.
    Wernicke, G.
    Woike, J. K.
    Wollbrant, C. E.
    Woodin, G.
    Wright, J. D.
    Xia, Q.
    Xie, Z.
    Yoon, S.
    Yuan, W.
    Yuan, L.
    Yucel, M.
    Zheng, Z.
    Zhou, H.
    Zogmaister, C.
    Zultan, R.
    Collaboration, Generalizability Tests Forecasting
    Examining the generalizability of research findings from archival data2022Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, nr 30, artikel-id e2120377119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability-for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples. 

  • 28. Dixit, Avinash
    et al.
    Weibull, Jörgen
    Political polarization2007Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, nr 18, s. 7351-7356Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Failures of government policies often provoke opposite reactions from citizens; some call for a reversal of the policy, whereas others favor its continuation in stronger form. We offer an explanation of such polarization, based on a natural bimodality of preferences in political and economic contexts and consistent with Bayesian rationality.

  • 29.
    Dong, Zhihua
    et al.
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap. Chongqing Univ, Coll Mat Sci & Engn, State Key Lab Mech Transmiss, Chongqing 400044, Peoples R China.;Chongqing Univ, Natl Engn Res Ctr Magnesium Alloys, Chongqing 400044, Peoples R China..
    Li, Wei
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Egenskaper.
    Schönecker, Stephan
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Jiang, Bin
    Chongqing Univ, Coll Mat Sci & Engn, State Key Lab Mech Transmiss, Chongqing 400044, Peoples R China.;Chongqing Univ, Natl Engn Res Ctr Magnesium Alloys, Chongqing 400044, Peoples R China..
    Vitos, Levente
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap. Uppsala Univ, Dept Phys & Astron, Div Mat Theory, SE-75120 Uppsala, Sweden.;Wigner Res Ctr Phys, Res Inst Solid State Phys & Opt, H-1525 Budapest, Hungary..
    Invariant plastic deformation mechanism in paramagnetic nickel-iron alloys2021Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, nr 14, artikel-id e2023181118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Invar anomaly is one of the most fascinating phenomena observed in magnetically ordered materials. Invariant thermal expansion and elastic properties have attracted substantial scientific attention and led to important technological solutions. By studying planar faults in the high-temperature magnetically disordered state of Ni1-cFec, here we disclose a completely different anomaly. An invariant plastic deformation mechanism is characterized by an unchanged stacking fault energy with temperature within wide concentration and temperature ranges. This anomaly emerges from the competing stability between the face-centered cubic and hexagonal close-packed structures and occurs in other paramagnetic or nonmagnetic systems whenever the structural balance exists. The present findings create a platform for tailoring high-temperature properties of technologically relevant materials toward plastic stability at elevated temperatures.

  • 30. Du, K.
    et al.
    Wu, Y. -W
    Lindroos, R.
    Liu, Y.
    Rózsa, B.
    Katona, G.
    Ding, J. B.
    Hellgren Kotaleski, Jeanette
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för datavetenskap och kommunikation (CSC). Stockholm Brain Institute, Karolinska Institute, 171 77 Solna, Sweden;bDepartment of Neuroscience, Karolinska Institute, 171 77 Solna.
    Cell-type–specific inhibition of the dendritic plateau potential in striatal spiny projection neurons2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 36, s. E7612-E7621Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Striatal spiny projection neurons (SPNs) receive convergent excitatory synaptic inputs from the cortex and thalamus. Activation of spatially clustered and temporally synchronized excitatory inputs at the distal dendrites could trigger plateau potentials in SPNs. Such supralinear synaptic integration is crucial for dendritic computation. However, how plateau potentials interact with subsequent excitatory and inhibitory synaptic inputs remains unknown. By combining computational simulation, two-photon imaging, optogenetics, and dual-color uncaging of glutamate and GABA, we demonstrate that plateau potentials can broaden the spatiotemporal window for integrating excitatory inputs and promote spiking. The temporal window of spiking can be delicately controlled by GABAergic inhibition in a cell-type–specific manner. This subtle inhibitory control of plateau potential depends on the location and kinetics of the GABAergic inputs and is achieved by the balance between relief and reestablishment of NMDA receptor Mg2+ block. These findings represent a mechanism for controlling spatiotemporal synaptic integration in SPNs.

  • 31.
    Duan, Lele
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Araujo, Carlos Moyses
    KTH, Skolan för bioteknologi (BIO), Teoretisk kemi och biologi.
    Ahlquist, Mårten S. G.
    KTH, Skolan för bioteknologi (BIO), Teoretisk kemi och biologi.
    Sun, Licheng
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Highly efficient and robust molecular ruthenium catalysts for water oxidation2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 39, s. 15584-15588Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Water oxidation catalysts are essential components of light-driven water splitting systems, which could convert water to H-2 driven by solar radiation (H2O + h nu -> 1/2O(2) + H-2). The oxidation of water (H2O -> 1/2O(2) + 2H(+) + 2e(-)) provides protons and electrons for the production of dihydrogen (2H(+) + 2e(-) -> H-2), a clean-burning and high-capacity energy carrier. One of the obstacles now is the lack of effective and robust water oxidation catalysts. Aiming at developing robust molecular Ru-bda (H(2)bda = 2,2'-bipyridine-6,6'-dicarboxylic acid) water oxidation catalysts, we carried out density functional theory studies, correlated the robustness of catalysts against hydration with the highest occupied molecular orbital levels of a set of ligands, and successfully directed the synthesis of robust Ru-bda water oxidation catalysts. A series of mononuclear ruthenium complexes [Ru(bda)L-2] (L = pyridazine, pyrimidine, and phthalazine) were subsequently synthesized and shown to effectively catalyze Ce-IV-driven [Ce-IV = Ce(NH4)(2()NO3)(6)] water oxidation with high oxygen production rates up to 286 s(-1) and high turnover numbers up to 55,400.

  • 32.
    Edin, Fredrik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Klingberg, Torkel
    Johansson, Par
    McNab, Fiona
    Tegner, Jesper
    Compte, Albert
    Mechanism for top-down control of working memory capacity2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 16, s. 6802-6807Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Working memory capacity, the maximum number of items that we can transiently store in working memory, is a good predictor of our general cognitive abilities. Neural activity in both dorsolateral prefrontal cortex and posterior parietal cortex has been associated with memory retention during visuospatial working memory tasks. The parietal cortex is thought to store the memories. However, the role of the dorsolateral prefrontal cortex, a top-down control area, during pure information retention is debated, and the mechanisms regulating capacity are unknown. Here, we propose that a major role of the dorsolateral prefrontal cortex in working memory is to boost parietal memory capacity. Furthermore, we formulate the boosting mechanism computationally in a biophysical cortical microcircuit model and derive a simple, explicit mathematical formula relating memory capacity to prefrontal and parietal model parameters. For physiologically realistic parameter values, lateral inhibition in the parietal cortex limits mnemonic capacity to a maximum of 2-7 items. However, at high loads inhibition can be counteracted by excitatory prefrontal input, thus boosting parietal capacity. Predictions from the model were confirmed in an fMRI study. Our results show that although memories are stored in the parietal cortex, interindividual differences in memory capacity are partly determined by the strength of prefrontal top-down control. The model provides a mechanistic framework for understanding top-down control of working memory and specifies two different contributions of prefrontal and parietal cortex to working memory capacity.

  • 33.
    Elmlund, Hans
    et al.
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik.
    Baraznenok, Vera
    Division of Metabolic Diseases, Karolinska Institutet.
    Lindahl, Martin
    Department of Molecular Biophysics, Lund University.
    Samuelsen, Camilla O.
    Department of Genetics, Institute of Molecular Biology, Copenhagen.
    Koeck, Philip J. B.
    KTH, Skolan för teknik och hälsa (STH).
    Holmberg, Steen
    Department of Genetics, Institute of Molecular Biology, Copenhagen.
    Hebert, Hans
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik.
    Gustafsson, Claes M.
    Division of Metabolic Diseases, Karolinska Institutet.
    The cyclin-dependent kinase 8 module sterically blocks Mediator interactions with RNA polymerase II2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 43, s. 15788-15793Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CDK8 (cyclin-dependent kinase 8), along with CycC, Med12, and Med13, form a repressive module (the Cdk8 module) that prevents RNA polymerase II (pol II) interactions with Mediator. Here, we report that the ability of the Cdk8 module to prevent pol II interactions is independent of the Cdk8-dependent kinase activity. We use electron microscopy and single-particle reconstruction to demonstrate that the Cdk8 module forms a distinct structural entity that binds to the head and middle region of Mediator, thereby sterically blocking interactions with pol II.

  • 34.
    Engquist, Björn
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk analys, NA.
    Osher, S
    One-sided difference schemes and transonic flow1980Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 77, nr 6, s. 3071-3074Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two one-sided conservation form difference approximations to a scalar one-dimensional convex conservation law are introduced. These are respectively of first- and second-order accuracy and each has the minimum possible band-width. They are nonlinearly stable, they converge only to solutions satisfying the entropy condition, and they have sharp monotone profiles. No such stable approximation of order higher than two is possible. Dimensional splitting algorithms are constructed and used to approximate the small-disturbance equation of transonic flow. These approximations are also nonlinearly stable and without nonphysical limit solutions.

  • 35.
    Frost Nylén, Johanna
    et al.
    Department of Neuroscience, Karolinska Institutet, Stockholm SE17177, Sweden.
    Hjorth, J. J. Johannes
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för elektroteknik och datavetenskap (EECS), Datavetenskap, Beräkningsvetenskap och beräkningsteknik (CST).
    Kozlov, Alexander
    KTH, Skolan för elektroteknik och datavetenskap (EECS). KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Neuroscience, Karolinska Institutet, Stockholm SE17177, Sweden.
    Carannante, Ilaria
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Datavetenskap, Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Datavetenskap, Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Neuroscience, Karolinska Institutet, Stockholm SE17177, Swede.
    Grillner, Sten
    Department of Neuroscience, Karolinska Institutet, Stockholm SE17177, Sweden.
    The roles of surround inhibition for the intrinsic function of the striatum, analyzed in silico2023Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, nr 45Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The basal ganglia are important for action initiation, selection, and motor learning. The input level, the striatum, receives input preferentially from the cortex and thalamus and is to 95% composed of striatal projection neurons (SPNs) with sparse GABAergic collaterals targeting distal dendrites of neighboring SPNs, in a distance-dependent manner. The remaining 5% are GABAergic and cholinergic interneurons. Our aim here is to investigate the role of surround inhibition for the intrinsic function of the striatum. Large-scale striatal networks of 20 to 40 thousand neurons were simulated with detailed multicompartmental models of different cell types, corresponding to the size of a module of the dorsolateral striatum, like the forelimb area (mouse). The effect of surround inhibition on dendritic computation and network activity was investigated, while groups of SPNs were activated. The SPN-induced surround inhibition in distal dendrites shunted effectively the corticostriatal EPSPs. The size of dendritic plateau-like potentials within the specific dendritic segment was both reduced and enhanced by inhibition, due to the hyperpolarized membrane potential of SPNs and the reversal-potential of GABA. On a population level, the competition between two subpopulations of SPNs was found to depend on the distance between the two units, the size of each unit, the activity level in each subgroup and the dopaminergic modulation of the dSPNs and iSPNs. The SPNs provided the dominating source of inhibition within the striatum, while the fast-spiking interneuron mainly had an initial effect due to short-term synaptic plasticity as shown in with ablation of the synaptic interaction.

  • 36.
    Galleano, Iacopo
    et al.
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Harms, Hendrik
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Choudhury, Koushik
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Khoo, Keith
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Pless, Stephan Alexander
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Na(v)1.52021Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, nr 33, artikel-id e2025320118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The voltage-gated sodium channel Nav1.5 initiates the cardiac action potential. Alterations of its activation and inactivation properties due to mutations can cause severe, life-threatening arrhythmias. Yet despite intensive research efforts, many functional aspects of this cardiac channel remain poorly understood. For instance, Nav1.5 undergoes extensive posttranslational modification in vivo, but the functional significance of these modifications is largely unexplored, especially under pathological conditions. This is because most conventional approaches are unable to insert metabolically stable posttranslational modification mimics, thus preventing a precise elucidation of the contribution by these modifications to channel function. Here, we overcome this limitation by using protein semisynthesis of Nav1.5 in live cells and carry out complementary molecular dynamics simulations. We introduce metabolically stable phosphorylation mimics on both wild-type (WT) and two pathogenic long-QT mutant channel backgrounds and decipher functional and pharmacological effects with unique precision. We elucidate the mechanism by which phosphorylation of Y1495 impairs steady-state inactivation in WT Nav1.5. Surprisingly, we find that while the Q1476R patient mutation does not affect inactivation on its own, it enhances the impairment of steady-state inactivation caused by phosphorylation of Y1495 through enhanced unbinding of the inactivation particle. We also show that both phosphorylation and patient mutations can impact Nav1.5 sensitivity toward the clinically used antiarrhythmic drugs quinidine and ranolazine, but not flecainide. The data highlight that functional effects of Nav1.5 phosphorylation can be dramatically amplified by patient mutations. Our work is thus likely to have implications for the interpretation of mutational phenotypes and the design of future drug regimens.

  • 37. Grinolds, Michael S.
    et al.
    Lobastov, Vladimir A.
    Weissenrieder, Jonas
    California Institute of Technology.
    Zewail, Ahmed H.
    Four-dimensional ultrafast electron microscopy of phase transitions2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 49, s. 18427-18431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Reported here is direct imaging (and diffraction) by using 4D ultrafast electron microscopy (UEM) with combined spatial and temporal resolutions. In the first phase of UEM, it was possible to obtain snapshot images by using timed, single-electron packets; each packet is free of space-charge effects. Here, we demonstrate the ability to obtain sequences of snapshots (”movies”) with atomic-scale spatial resolution and ultrashort temporal resolution. Specifically, it is shown that ultrafast metal-insulator phase transitions can be studied with these achieved spatial and temporal resolutions. The diffraction (atomic scale) and images (nanometer scale) we obtained manifest the structural phase transition with its characteristic hysteresis, and the time scale involved (100 fs) is now studied by directly monitoring coordinates of the atoms themselves.

  • 38.
    Hafstrand, Ida
    et al.
    Karolinska Inst, Dept Med Solna, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Div Infect Dis, SE-17176 Stockholm, Sweden..
    Sayitoglu, Ece Canan
    Nova Southeastern Univ, Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33301 USA..
    Apavaloaei, Anca
    Jacobs Univ Bremen, Dept Life Sci & Chem, D-28759 Bremen, Germany..
    Josey, Benjamin John
    Nova Southeastern Univ, Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33301 USA..
    Sun, Renhua
    Karolinska Inst, Dept Med Solna, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Div Infect Dis, SE-17176 Stockholm, Sweden..
    Han, Xiao
    Karolinska Inst, Dept Med Solna, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Div Infect Dis, SE-17176 Stockholm, Sweden..
    Pellegrino, Sara
    Univ Milan, Gen & Organ Chem Sect, Dept Pharmaceut Sci, I-20133 Milan, Italy..
    Ozkazanc, Didem
    Nova Southeastern Univ, Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33301 USA..
    Potens, Renee
    Nova Southeastern Univ, Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33301 USA..
    Janssen, Linda
    Jacobs Univ Bremen, Dept Life Sci & Chem, D-28759 Bremen, Germany..
    Nilvebrant, Johan
    KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nygren, Per-Åke
    KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Sandalova, Tatyana
    Karolinska Inst, Dept Med Solna, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Div Infect Dis, SE-17176 Stockholm, Sweden..
    Springer, Sebastian
    Jacobs Univ Bremen, Dept Life Sci & Chem, D-28759 Bremen, Germany..
    Georgoudaki, Anna-Maria
    Nova Southeastern Univ, Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33301 USA..
    Duru, Adil Doganay
    Karolinska Inst, Dept Med Solna, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Div Infect Dis, SE-17176 Stockholm, Sweden.;Nova Southeastern Univ, Cell Therapy Inst, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33301 USA..
    Achour, Adnane
    Karolinska Inst, Dept Med Solna, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Div Infect Dis, SE-17176 Stockholm, Sweden..
    Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 11, s. 5055-5060Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    MHC-I epitope presentation to CD8(+) T cells is directly dependent on peptide loading and selection during antigen processing. However, the exact molecular bases underlying peptide selection and binding by MHC-I remain largely unknown. Within the peptide-loading complex, the peptide editor tapasin is key to the selection of MHC-I-bound peptides. Here, we have determined an ensemble of crystal structures of MHC-I in complex with the peptide exchange-associated dipeptide GL, as well as the tapasin-associated scoop loop, alone or in combination with candidate epitopes. These results combined with mutation analyses allow us to propose a molecular model underlying MHC-I peptide selection by tapasin. The N termini of bound peptides most probably bind first in the N-terminal and middle region of the MHC-I peptide binding cleft, upon which the peptide C termini are tested for their capacity to dislodge the tapasin scoop loop from the F pocket of the MHC-I cleft. Our results also indicate important differences in peptide selection between different MHC-I alleles.

  • 39.
    Hallman, Kristina
    et al.
    KTH, Tidigare Institutioner (före 2005), Kemi.
    Frölander, Anders
    KTH, Tidigare Institutioner (före 2005), Kemi.
    Wondimagegn, Tebikie
    KTH, Tidigare Institutioner (före 2005), Kemi.
    Svensson, Mats
    KTH, Tidigare Institutioner (före 2005), Kemi.
    Moberg, Christina
    KTH, Tidigare Institutioner (före 2005), Kemi.
    OH–Pd(0) Interaction as a Stabilizing Factor in Palladium-Catalyzed Allylic Alkylations2004Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, nr 15, s. 5400-5404Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In palladium-catalyzed alkylations of allylic acetates with malonate as nucleophile, catalysts with oxazoline ligands bearing hydroxymethyl substituents in 4-position have been shown by density functional theory computations to undergo a conformational change on nucleophilic attack, which is accompanied by reduction of Pd(II) to Pd(0). The conformations of the Pd(0) complexes were shown to be governed by the presence of a hydrogen bond with the metal center acting as a hydrogen bond acceptor. The conformational change, which is absent in catalysts with O-alkylated analogs, largely affects the enantioselectivity of the catalytic process. This process is a previously uninvestigated example of where this type of weak hydrogen bond has been shown to influence the stereochemistry of a chemical reaction.

  • 40. Henrion, Ulrike
    et al.
    Renhorn, Jakob
    Börjesson, Sara I.
    Nelson, Erin M.
    Schwaiger, Christine S.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Bjelkmar, Pär
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Wallner, Björn
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Elinder, Fredrik
    Tracking a complete voltage-sensor cycle with metal-ion bridges2012Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 22, s. 8552-8557Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

  • 41. Hertzberg, M.
    et al.
    Aspeborg, H.
    Schrader, J.
    Andersson, A.
    Erlandsson, R.
    Blomqvist, K.
    Bhalerao, R.
    Uhlén, Mathias
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Teeri, Tuula T.
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Lundeberg, Joakim
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Sundberg, B.
    Nilsson, Peter
    KTH, Tidigare Institutioner (före 2005), Bioteknologi.
    Sandberg, G.
    A transcriptional roadmap to wood formation2001Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 98, nr 25, s. 14732-14737Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The large vascular meristem of poplar trees with its highly organized secondary xylem enables the boundaries between different developmental zones to be easily distinguished. This property of wood-forming tissues allowed us to determine a unique tissue-specific transcript profile for a well defined developmental gradient. RNA was prepared from different developmental stages of xylogenesis for DNA microarray analysis by using a hybrid aspen unigene set consisting of 2,995 expressed sequence tags. The analysis revealed that the genes encoding lignin and cellulose biosynthetic enzymes, as well as a number of transcription factors and other potential regulators of xylogenesis, are under strict developmental stage-specific transcriptional regulation.

  • 42. Hess, Berk
    et al.
    van der Vegt, Nico F A
    Cation specific binding with protein surface charges2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 32, s. 13296-300Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Biological organization depends on a sensitive balance of noncovalent interactions, in particular also those involving interactions between ions. Ion-pairing is qualitatively described by the law of "matching water affinities." This law predicts that cations and anions (with equal valence) form stable contact ion pairs if their sizes match. We show that this simple physical model fails to describe the interaction of cations with (molecular) anions of weak carboxylic acids, which are present on the surfaces of many intra- and extracellular proteins. We performed molecular simulations with quantitatively accurate models and observed that the order K(+) < Na(+) < Li(+) of increasing binding affinity with carboxylate ions is caused by a stronger preference for forming weak solvent-shared ion pairs. The relative insignificance of contact pair interactions with protein surfaces indicates that thermodynamic stability and interactions between proteins in alkali salt solutions is governed by interactions mediated through hydration water molecules.

  • 43.
    Heusser, Stephanie A.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Lycksell, Marie
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Wang, Xueqing
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    McComas, Sarah E.
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Lindahl, Erik
    KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Centra, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 42, s. 10672-10677Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to similar to 30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.

  • 44.
    Hjorth, J. J. Johannes
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för elektroteknik och datavetenskap (EECS).
    Kozlov, Alexander
    KTH, Skolan för elektroteknik och datavetenskap (EECS). KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Carannante, Ilaria
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Datavetenskap, Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nylen, Johanna Frost
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Lindroos, Robert
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Johansson, Yvonne
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Tokarska, Anna
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Dorst, Matthijs C.
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Suryanarayana, Shreyas M.
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Silberberg, Gilad
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Hellgren Kotaleski, Jeanette
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för elektroteknik och datavetenskap (EECS). Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    Grillner, Sten
    Karolinska Inst, Dept Neurosci, SE-17165 Stockholm, Sweden..
    The microcircuits of striatum in silico2020Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, nr 17, s. 9554-9565Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, somadendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.

  • 45. Ho, Andrew T. V.
    et al.
    Palla, Adelaida R.
    Blake, Matthew R.
    Yucel, Nora D.
    Wang, Yu Xin
    Magnusson, Klas E. G.
    KTH, Skolan för elektro- och systemteknik (EES), Centra, ACCESS Linnaeus Centre. KTH, Skolan för elektro- och systemteknik (EES), Signalbehandling. Stanford Sch Med, USA.
    Holbrook, Colin A.
    Kraft, Peggy E.
    Delp, Scott L.
    Blau, Helen M.
    Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 26, s. 6675-6684Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1. Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain-or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.

  • 46. Holmström, Erik
    et al.
    Nordström, Lars
    Bergqvist, Lars
    KTH, Tidigare Institutioner (före 2005), Materialvetenskap.
    Skubic, Björn
    Hjörvarsson, Björgvin
    Abrikosov, Igor A.
    Svedlindh, Peter
    Eriksson, Olle
    On the sharpness of the interfaces in metallic multilayers2004Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, nr 14, s. 4742-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We show that the three most relevant magnetic properties (magnetic moment, critical temperature, and interlayer exchange coupling) of metallic multilayers can be reproduced with good accuracy by first principles theory, provided that the picture of atomically sharp interfaces is abandoned and one allows instead for both interface alloying and interface roughness. The interface of a metallic multilayer (exemplified by the Fe/V system) is demonstrated to, at best, have interdiffusion essentially over two to three atomic layers on each side of the interface. Our conclusions are the result of combining experimental work with theoretical modeling, and we argue that this approach is the best avenue to obtain accurate information about the interface quality of metallic multilayers.

  • 47.
    Howard, Rebecca J
    et al.
    University of Texas.
    Murail, Samuel
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Ondricek, Kathryn E
    University of Texas.
    Corringer, Pierre-Jean
    Institut Pasteur.
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik.
    Trudell, James R
    Stanford University.
    Harris, R Adron
    University of Texas.
    Structural basis for alcohol modulation of a pentameric ligand-gated ion channel2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 29, s. 12149-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the "linking tunnel." These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member.

  • 48.
    Hoyer, Wolfgang
    et al.
    Department of Medical Biochemistry, Swedish Nuclear Magnetic Resonance Center, University of Gothenburg.
    Grönwall, Caroline
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Jonsson, Andreas
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Härd, Torleif
    Department of Medical Biochemistry, Swedish Nuclear Magnetic Resonance Center, University of Gothenburg.
    Stabilization of a beta-hairpin in monomeric Alzheimer´s amyloid beta-peptide inhibits amyloid formation2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 13, s. 5099-5104Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1–40) in complex with the phage-display selected affibody protein ZAβ3, a binding protein of nanomolar affinity. Bound Aβ(1–40) features a β-hairpin comprising residues 17–36, providing the first high-resolution structure of Aβ in β conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar Aβ. ZAβ3 stabilizes the β-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity. Consequently, ZAβ3 acts as a stoichiometric inhibitor of Aβ fibrillation. The selected Aβ conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.

  • 49. Huang, Mingtao
    et al.
    Bai, Yunpeng
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. East China University of Science and Technology, China.
    Sjöström, Staffan L.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hallström, Björn M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Liu, Zihe
    Petranovic, Dina
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Technical University of Denmark, Denmark .
    Jönsson, Håkan N.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Andersson Svahn, Helene
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden; Technical University of Denmark, Denmark.
    Microfluidic screening and whole-genome sequencing identifies mutations associated with improved protein secretion by yeast2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 34, s. E4689-E4696Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    There is an increasing demand for biotech-based production of recombinant proteins for use as pharmaceuticals in the food and feed industry and in industrial applications. Yeast Saccharomyces cerevisiae is among preferred cell factories for recombinant protein production, and there is increasing interest in improving its protein secretion capacity. Due to the complexity of the secretory machinery in eukaryotic cells, it is difficult to apply rational engineering for construction of improved strains. Here we used highthroughput microfluidics for the screening of yeast libraries, generated by UV mutagenesis. Several screening and sorting rounds resulted in the selection of eight yeast clones with significantly improved secretion of recombinant α-amylase. Efficient secretion was genetically stable in the selected clones. We performed wholegenome sequencing of the eight clones and identified 330 mutations in total. Gene ontology analysis of mutated genes revealed many biological processes, including some that have not been identified before in the context of protein secretion. Mutated genes identified in this study can be potentially used for reverse metabolic engineering, with the objective to construct efficient cell factories for protein secretion. The combined use of microfluidics screening and whole-genome sequencing to map the mutations associated with the improved phenotype can easily be adapted for other products and cell types to identify novel engineering targets, and this approach could broadly facilitate design of novel cell factories.

  • 50.
    Häggmark, Ilian
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biomedicinsk fysik och röntgenfysik. Univ Museum, Univ Tokyo, Tokyo 1130033, Japan..
    Shaker, Kian
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biomedicinsk fysik och röntgenfysik. Stanford Univ, Dept Radiol, Stanford, CA 94305 USA..
    Nyren, Sven
    Karolinska Inst, Dept Mol Med & Surg, S-17176 Solna, Sweden.;Karolinska Univ Hosp, Dept Radiol, S-17176 Solna, Sweden..
    Al-Amiry, Bariq
    Karolinska Univ Hosp, Dept Radiol, S-17176 Solna, Sweden.;Karolinska Inst, Dept Clin Sci, Intervent & Technol, S-17177 Stockholm, Sweden..
    Abadi, Ehsan
    Duke Univ Med Ctr, Ctr Virtual Imaging Trials, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA..
    Segars, William P.
    Duke Univ Med Ctr, Ctr Virtual Imaging Trials, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA..
    Samei, Ehsan
    Duke Univ Med Ctr, Ctr Virtual Imaging Trials, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA..
    Hertz, Hans
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biomedicinsk fysik och röntgenfysik.
    Phase-contrast virtual chest radiography2023Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, nr 1, artikel-id e2210214120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Respiratory X-ray imaging enhanced by phase contrast has shown improved airway visualization in animal models. Limitations in current X-ray technology have nevertheless hindered clinical translation, leaving the potential clinical impact an open question. Here, we explore phase-contrast chest radiography in a realistic in silico framework. Specifically, we use preprocessed virtual patients to generate in silico chest radiographs by Fresnel-diffraction simulations of X-ray wave propagation. Following a reader study conducted with clinical radiologists, we predict that phase-contrast edge enhancement will have a negligible impact on improving solitary pulmonary nodule detection (6 to 20 mm). However, edge enhancement of bronchial walls visualizes small airways (<2 mm), which are invisible in conventional radiography. Our results show that phase-contrast chest radiography could play a future role in observing small-airway obstruction (e.g., relevant for asthma or early-stage chronic obstructive pulmonary disease), which cannot be directly visualized using current clinical methods, thereby motivating the experimental development needed for clinical translation. Finally, we discuss quantitative requirements on distances and X-ray source/detector specifications for clinical implementation of phase-contrast chest radiography.

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