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  • 1. Agerberth, B
    et al.
    Gunne, H
    Odeberg, Jacob
    KTH, Tidigare Institutioner                               , 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.1995Inngår 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. 195-9Artikkel i tidsskrift (Fagfellevurdert)
    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 oscillations2001Inngår 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. 13420-13424Artikkel i tidsskrift (Fagfellevurdert)
    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 problems2008Inngår 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. 15253-15257Artikkel i tidsskrift (Fagfellevurdert)
    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 vivo2017Inngår 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-E1421Artikkel i tidsskrift (Fagfellevurdert)
    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. 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.
    Ermund, A.
    Johansson, B.R.
    Koeck, Philip J. B.
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik (Stängd 20130701).
    Hebert, Hans
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik (Stängd 20130701).
    Hansson, G.C.
    Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin2012Inngår 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. 5645-5650Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6.
    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 ceria2006Inngår 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. 3518-3521Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 7. 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 pressure2008Inngår 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. 20627-20630Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 8. Attems, Johannes
    et al.
    Alpar, Alan
    Spence, Lauren
    McParland, Shane
    Heikenwalder, Mathias
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). 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 differentiation2012Inngår 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. 6259-6264Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9.
    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 sclerosis2016Inngår 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. 2188-2193Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 10.
    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 principles2008Inngår 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. 7177-7781Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 11.
    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 subtypes2018Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490Artikkel i tidsskrift (Fagfellevurdert)
  • 12. 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 medium2007Inngår 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. 20173-20176Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 13.
    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 rabbits2018Inngår 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. 7380-7385Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 14.
    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 elegans2018Inngår 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. 11537-11542Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 15.
    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 effect2019Inngår 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. 4877-4882Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16.
    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 syringae2004Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, s. 8239-8244Artikkel i tidsskrift (Fagfellevurdert)
  • 17.
    Danielsson, Frida
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Skogs, Marie
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). 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 (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model2013Inngår 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. 6853-6858Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 18.
    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.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Ytkemi.
    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 g2011Inngår 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. 7997-8002Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 19. Dixit, Avinash
    et al.
    Weibull, Jörgen
    Political polarization2007Inngår 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. 7351-7356Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 20. 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 neurons2017Inngår 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-E7621Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 21.
    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 oxidation2012Inngår 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. 15584-15588Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 22.
    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 capacity2009Inngår 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. 6802-6807Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 23.
    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 II2006Inngår 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. 15788-15793Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 24.
    Engquist, Björn
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk analys, NA.
    Osher, S
    One-sided difference schemes and transonic flow1980Inngår 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. 3071-3074Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 25. Grinolds, Michael S.
    et al.
    Lobastov, Vladimir A.
    Weissenrieder, Jonas
    California Institute of Technology.
    Zewail, Ahmed H.
    Four-dimensional ultrafast electron microscopy of phase transitions2006Inngår 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. 18427-18431Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 26.
    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 tapasin2019Inngår 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. 5055-5060Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 27.
    Hallman, Kristina
    et al.
    KTH, Tidigare Institutioner, Kemi.
    Frölander, Anders
    KTH, Tidigare Institutioner, Kemi.
    Wondimagegn, Tebikie
    KTH, Tidigare Institutioner, Kemi.
    Svensson, Mats
    KTH, Tidigare Institutioner, Kemi.
    Moberg, Christina
    KTH, Tidigare Institutioner, Kemi.
    OH–Pd(0) Interaction as a Stabilizing Factor in Palladium-Catalyzed Allylic Alkylations2004Inngår 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. 5400-5404Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 28. 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 bridges2012Inngår 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. 8552-8557Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 29. Hertzberg, M.
    et al.
    Aspeborg, H.
    Schrader, J.
    Andersson, A.
    Erlandsson, R.
    Blomqvist, K.
    Bhalerao, R.
    Uhlén, Mathias
    KTH, Tidigare Institutioner, Bioteknologi.
    Teeri, Tuula T.
    KTH, Tidigare Institutioner, Bioteknologi.
    Lundeberg, Joakim
    KTH, Tidigare Institutioner, Bioteknologi.
    Sundberg, B.
    Nilsson, Peter
    KTH, Tidigare Institutioner, Bioteknologi.
    Sandberg, G.
    A transcriptional roadmap to wood formation2001Inngår 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. 14732-14737Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 30. Hess, Berk
    et al.
    van der Vegt, Nico F A
    Cation specific binding with protein surface charges2009Inngår 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. 13296-300Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 31.
    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 cavity2018Inngår 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. 10672-10677Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 32. 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 strength2017Inngår 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. 6675-6684Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 33. Holmström, Erik
    et al.
    Nordström, Lars
    Bergqvist, Lars
    KTH, Tidigare Institutioner, Materialvetenskap.
    Skubic, Björn
    Hjörvarsson, Björgvin
    Abrikosov, Igor A.
    Svedlindh, Peter
    Eriksson, Olle
    On the sharpness of the interfaces in metallic multilayers2004Inngår 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-Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 34.
    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 channel2011Inngår 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. 12149-54Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 35.
    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 formation2008Inngår 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. 5099-5104Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 36. 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 yeast2015Inngår 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-E4696Artikkel i tidsskrift (Annet vitenskapelig)
    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.

  • 37. Isaev, E. I.
    et al.
    Skorodumova, N. V.
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Vekilov, Y. K.
    Johansson, Börje
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Dynamical stability of Fe-H in the Earth's mantle and core regions2007Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, nr 22, s. 9168-9171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The core extends from the depth of 2,900 km to the center of the Earth and is composed mainly of an iron-rich alloy with nickel, with 10% of the mass comprised of lighter elements like hydrogen, but the exact composition is uncertain. We present a quantum mechanical first-principles study of the dynamical stability of FeH phases and their phonon densities of states at high pressure. Our free-energy calculations reveal a phonon-driven stabilization of dhcp FeH at low pressures, thus resolving the present contradiction between experimental observations and theoretical predictions. Calculations reveal a complex phase diagram for FeH under pressure with a dhcp -> hcp -> fcc sequence of structural transitions.

  • 38.
    Jegerschöld, Caroline
    et al.
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik (Stängd 20130701).
    Paweizik, Sven-Christian
    Purhonen, Pasi
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik (Stängd 20130701).
    Bhakat, Priyaranian
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik (Stängd 20130701).
    Gheorghe, Karina Roxana
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik (Stängd 20130701).
    Gyobu, Nobuhiko
    Mitsuoka, Kaoru
    Morgenstern, Ralf
    Jakobsson, Per-Johan
    Hebert, Hans
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik (Stängd 20130701).
    Structural basis for induced formation of the inflammatory mediator prostaglandin E-22008Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 32, s. 11110-11115Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prostaglandins (PG) are bioactive lipids produced from arachidonic acid via the action of cyclooxygenases and terminal PG synthases. Microsomal prostaglandin E synthase 1 (MPGES1) constitutes an inducible glutathione-dependent integral membrane protein that catalyzes the oxidoreduction of cyclooxygenase derived PGH(2) into PGE(2). MPGES1 has been implicated in a number of human diseases or pathological conditions, such as rheumatoid arthritis, fever, and pain, and is therefore regarded as a primary target for development of novel antiinflammatory drugs. To provide a structural basis for insight in the catalytic mechanism, we determined the structure of MPGES1 in complex with glutathione by electron crystallography from 2D crystals induced in the presence of phospholipids. Together with results from site-directed mutagenesis and activity measurements, we can thereby demonstrate the role of specific amino acid residues. Glutathione is found to bind in a U-shaped conformation at the interface between subunits in the protein trimer. It is exposed to a site facing the lipid bilayer, which forms the specific environment for the oxidoreduction of PGH(2) to PGE(2) after displacement of the cytoplasmic half of the IN-terminal transmembrane helix. Hence, insight into the dynamic behavior of MPGES1 and homologous membrane proteins in inflammation and detoxification is provided.

  • 39. Jo, Minho
    et al.
    Koo, Yang Mo
    Lee, Byeong-Joo
    Johansson, Börje
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Vitos, Levente
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Kwon, Se Kyun
    Theory for plasticity of face-centered cubic metals2014Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 18, s. 6560-6565Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The activation of plastic deformation mechanisms determines the mechanical behavior of crystalline materials. However, the complexity of plastic deformation and the lack of a unified theory of plasticity have seriously limited the exploration of the full capacity of metals. Current efforts to design high-strength structural materials in terms of stacking fault energy have not significantly reduced the laborious trial and error works on basic deformation properties. To remedy this situation, here we put forward a comprehensive and transparent theory for plastic deformation of face-centered cubic metals. This is based on a microscopic analysis that, without ambiguity, reveals the various deformation phenomena and elucidates the physical fundaments of the currently used phenomenological correlations. We identify an easily accessible single parameter derived from the intrinsic energy barriers, which fully specifies the potential diversity of metals. Based entirely on this parameter, a simple deformation mode diagram is shown to delineate a series of convenient design criteria, which clarifies a wide area of material functionality by texture control.

  • 40.
    Johansson, Anna C V
    et al.
    Stockholm University.
    Lindahl, Erik
    Stockholm University.
    Protein contents in biological membranes can explain abnormal solvation of charged and polar residues.2009Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 37, s. 15684-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transmembrane helices are generally believed to insert into membranes based on their hydrophobicity. Nevertheless, there are important exceptions where polar residues have great functional importance, for instance the S4 helix of voltage-gated ion channels. It has been shown experimentally that insertion can be accomplished by hydrophobic counterbalance, predicting an arginine insertion cost of only 2.5 kcal/mol, compared with 14.9 kcal/mol in cyclohexane. Previous simulations of pure bilayers have produced values close to the pure hydrocarbon, which has lead to spirited discussion about the experimental conditions. Here, we have performed computer simulations of models better mimicking biological membranes by explicitly including protein helices at mass fractions from 15% to 55%, as well as an actual translocon. This has a striking effect on the solvation free energy of arginine. With some polar residues present, the solvation cost comes close to experimental observation at approximately 30% mass fraction, and negligible at 40%. In the presence of a translocon in the membrane, the cost of inserting arginine next to the lateral gate can be as low as 3-5 kcal/mol. The effect is mainly due to the extra helices making it easier to retain hydration water. These results offer a possible explanation for the discrepancy between the in vivo hydrophobicity scale and computer simulations and highlight the importance of the high protein contents in membranes. Although many membrane proteins are stable in pure bilayers, such simplified models might not be sufficiently accurate for insertion of polar or charged residues in biological membranes.

  • 41. Kadas, K.
    et al.
    Vitos, Levente
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Johansson, Börje
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Stability of body-centered cubic iron-magnesium alloys in the Earth's inner core2009Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 37, s. 15560-15562Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The composition and the structure of the Earth's solid inner core are still unknown. Iron is accepted to be the main component of the core. Lately, the body-centered cubic (bcc) phase of iron was suggested to be present in the inner core, although its stability at core conditions is still in discussion. The higher density of pure iron compared with that of the Earth's core indicates the presence of light element(s) in this region, which could be responsible for the stability of the bcc phase. However, so far, none of the proposed composition models were in full agreement with seismic observations. The solubility of magnesium in hexagonal Fe has been found to increase significantly with increasing pressure, suggesting that Mg can also be an important element in the core. Here, we report a first-principles density functional study of bcc Fe-Mg alloys at core pressures and temperatures. We show that at core conditions, 5-10 atomic percent Mg stabilizes the bcc Fe both dynamically and thermodynamically. Our calculated density, elastic moduli, and sound velocities of bcc Fe-Mg alloys are consistent with those obtained from seismology, indicating that the bcc-structured Fe-Mg alloy is a possible model for the Earth's inner core.

  • 42.
    Kamada, Ayaka
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Mekanik. KTH, Skolan för teknikvetenskap (SCI), Centra, Linné Flow Center, FLOW.
    Mittal, Nitesh
    KTH, Skolan för teknikvetenskap (SCI), Mekanik. KTH, Skolan för kemivetenskap (CHE), Centra, Wallenberg Wood Science Center. KTH, Skolan för teknikvetenskap (SCI), Centra, Linné Flow Center, FLOW.
    Söderberg, L. Daniel
    KTH, Skolan för teknikvetenskap (SCI), Mekanik. KTH, Skolan för teknikvetenskap (SCI), Centra, Linné Flow Center, FLOW. KTH, Skolan för kemivetenskap (CHE), Centra, Wallenberg Wood Science Center.
    Ingverud, Tobias
    KTH, Skolan för kemivetenskap (CHE), Centra, Wallenberg Wood Science Center. KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknologi.
    Ohm, Wiebke
    Roth, Stephan V.
    KTH, Skolan för kemivetenskap (CHE), Fiber- och polymerteknologi. Photon Science, Deutsches Elektronen-Synchrotron (DESY), D-22607 Hamburg, Germany.
    Lundell, Fredrik
    KTH, Skolan för kemivetenskap (CHE), Centra, Wallenberg Wood Science Center. KTH, Skolan för teknikvetenskap (SCI), Centra, Linné Flow Center, FLOW. KTH, Skolan för teknikvetenskap (SCI), Mekanik.
    Lendel, Christofer
    KTH, Skolan för kemivetenskap (CHE), Kemi.
    Flow-assisted assembly of nanostructured protein microfibers2017Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 6, s. 1232-1237Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Some of the most remarkable materials in nature are made from proteins. The properties of these materials are closely connected to the hierarchical assembly of the protein building blocks. In this perspective, amyloid-like protein nanofibrils (PNFs) have emerged as a promising foundation for the synthesis of novel bio-based materials for a variety of applications. Whereas recent advances have revealed the molecular structure of PNFs, the mechanisms associated with fibril-fibril interactions and their assembly into macroscale structures remain largely unexplored. Here, we show that whey PNFs can be assembled into microfibers using a flow-focusing approach and without the addition of plasticizers or cross-linkers. Microfocus small-angle X-ray scattering allows us to monitor the fibril orientation in the microchannel and compare the assembly processes of PNFs of distinct morphologies. We find that the strongest fiber is obtained with a sufficient balance between ordered nanostructure and fibril entanglement. The results provide insights in the behavior of protein nanostructures under laminar flow conditions and their assembly mechanism into hierarchical macroscopic structures.

  • 43. Karthigeyan, Dhanasekaran
    et al.
    Siddhanta, Soumik
    Kishore, Annavarapu Hari
    Perumal, Sathya S. R. R.
    KTH, Skolan för bioteknologi (BIO), Teoretisk kemi och biologi.
    Ågren, Hans
    KTH, Skolan för bioteknologi (BIO), Teoretisk kemi och biologi.
    Sudevan, Surabhi
    Bhat, Akshay V.
    Balasubramanyam, Karanam
    Subbegowda, Rangappa Kanchugarakoppal
    Kundu, Tapas K.
    Narayana, Chandrabhas
    SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool2014Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 29, s. 10416-10421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We demonstrate the use of surface-enhanced Raman spectroscopy (SERS) as an excellent tool for identifying the binding site of small molecules on a therapeutically important protein. As an example, we show the specific binding of the common antihypertension drug felodipine to the oncogenic Aurora A kinase protein via hydrogen bonding interactions with Tyr-212 residue to specifically inhibit its activity. Based on SERS studies, molecular docking, molecular dynamics simulation, biochemical assays, and point mutation-based validation, we demonstrate the surface-binding mode of this molecule in two similar hydrophobic pockets in the Aurora A kinase. These binding pockets comprise the same unique hydrophobic patches that may aid in distinguishing human Aurora A versus human Aurora B kinase in vivo. The application of SERS to identify the specific interactions between small molecules and therapeutically important proteins by differentiating competitive and noncompetitive inhibition demonstrates its ability as a complementary technique. We also present felodipine as a specific inhibitor for oncogenic Aurora A kinase. Felodipine retards the rate of tumor progression in a xenografted nude mice model. This study reveals a potential surface pocket that may be useful for developing small molecules by selectively targeting the Aurora family kinases.

  • 44. Kenney, John
    et al.
    Kutcherov, Vladimir
    Russian State University of Oil and Gas,Moscow, Russia.
    Bendeliani, Nikolay
    Alekseev, Vladimir
    The evolution of multicomponent systems at high pressure: Vi. The thermodynamic stability of the hydrogen-carbon system: The genesis of hydrocarbons and the origin of petroleum2002Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, nr 17, s. 10976-10981Artikkel i tidsskrift (Fagfellevurdert)
  • 45. Kim, D. Y.
    et al.
    Scheicher, R. H.
    Lebegue, S.
    Prasongkit, J.
    Arnaud, B.
    Alouani, M.
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap.
    Crystal structure of the pressure-induced metallic phase of SiH4 from ab initio theory2008Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 43, s. 16454-16459Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metallization of pure solid hydrogen is of great interest, not least because it could lead to high-temperature superconductivity, but it continues to be an elusive goal because of great experimental challenges. Hydrogen-rich materials, in particular, CH4, SiH4, and GeH4, provide an opportunity to study related phenomena at experimentally achievable pressures, and they too are expected to be high-temperature superconductors. Recently, the emergence of a metallic phase has been observed in silane for pressures just above 60 GPa. However, some uncertainty exists about the crystal structure of the discovered metallic phase. Here, we show by way of elimination, that a single structure that possesses all of the required characteristics of the experimentally observed metallic phase of silane from a pool of plausible candidates can be identified. Our density functional theory and GW calculations show that a structure with space group P4/nbm is metallic at pressures > 60 GPa. Based on phonon calculations, we furthermore demonstrate that the P4/nbm structure is dynamically stable at > 43 GPa and becomes the ground state at 97 GPa when zero-point energy contributions are considered. These findings could lead the way for further theoretical analysis of metallic phases of hydrogen-rich materials and stimulate experimental studies.

  • 46. Kim, D. Y.
    et al.
    Scheicher, R. H.
    Mao, H. K.
    Kang, T. W.
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    General trend for pressurized superconducting hydrogen-dense materials2010Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 7, s. 2793-2796Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The long-standing prediction that hydrogen can assume a metallic state under high pressure, combined with arguments put forward more recently that this state might even be superconducting up to high temperatures, continues to spur tremendous research activities toward the experimental realization of metallic hydrogen. These efforts have however so far been impeded by the enormous challenges associated with the exceedingly large required pressure. Hydrogen-dense materials, of the MH4 form ( where M can be, e. g., Si, Ge, or Sn) or of the MH3 form ( with M being, e. g., Al, Sc, Y, or La), allow for the rather exciting opportunity to carry out a proxy study of metallic hydrogen and associated high-temperature superconductivity at pressures within the reach of current techniques. At least one experimental report indicates that a superconducting state might have been observed already in SiH4, and several theoretical studies have predicted superconductivity in pressurized hydrogen-rich materials; however, no systematic dependence on the applied pressure has yet been identified so far. In the present work, we have used first-principles methods in an attempt to predict the superconducting critical temperature (T-c) as a function of pressure ( P) for three metal-hydride systems of the MH3 form, namely ScH3, YH3, and LaH3. By comparing the obtained results, we are able to point out a general trend in the T-c-dependence on P. These gained insights presented here are likely to stimulate further theoretical studies of metallic phases of hydrogen-dense materials and should lead to new experimental investigations of their superconducting properties.

  • 47.
    Korzhavyi, Pavel A.
    et al.
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Materialteknologi.
    Soroka, Inna L.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Fysikalisk kemi.
    Isaev, Eyvaz I.
    Lilja, Christina
    Johansson, Börje
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik.
    Exploring monovalent copper compounds with oxygen and hydrogen2012Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 3, s. 686-689Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    New important applications of copper metal, e.g., in the areas of hydrogen production, fuel cell operation, and spent nuclear fuel disposal, require accurate knowledge of the physical and chemical properties of stable and metastable copper compounds. Among the copper(I) compounds with oxygen and hydrogen, cuprous oxide Cu(2)O is the only one stable and the best studied. Other such compounds are less known (CuH) or totally unknown (CuOH) due to their instability relative to the oxide. Here we combine quantum-mechanical calculations with experimental studies to search for possible compounds of monovalent copper. Cuprous hydride (CuH) and cuprous hydroxide (CuOH) are proved to exist in solid form. We establish the chemical and physical properties of these compounds, thereby filling the existing gaps in our understanding of hydrogen- and oxygen-related phenomena in Cu metal.

  • 48. Kotmool, K.
    et al.
    Li, B.
    Chakraborty, S.
    Bovornratanaraks, T.
    Luo, W.
    Mao, H. -K
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik. Uppsala Univ, Sweden.
    High pressure-induced distortion in face-centered cubic phase of thallium2016Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 40, s. 11143-11147Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The complex and unusual high-pressure phase transition of III-A (i.e. Al, Ga, and In) metals have been investigated in the last several decades because of their interesting periodic table position between the elements having metallic and covalent bonding. Our present first principles-based electronic structure calculations and experimental investigation have revealed the unusual distortion in face-centered cubic (f.c.c.) phase of the heavy element thallium (Tl) induced by the high pressure. We have predicted body-centered tetragonal (b.c.t) phase at 83 GPa using an evolutionary algorithm coupled with ab initio calculations, and this prediction has been confirmed with a slightly distorted parameter (√2 x a - c)/c lowered by 1% using an angle-dispersive X-ray diffraction technique. The density functional theory (DFT)-based calculations suggest that s-p mixing states and the valence-core overlapping of 6s and 5d states play the most important roles for the phase transitions along the pathway h.c.p → f.c.c. → b.c.t.

  • 49. Kotmool, Komsilp
    et al.
    Kaewmaraya, Thanayut
    Chakraborty, Sudip
    Anversa, Jonas
    Bovornratanaraks, Thiti
    Luo, Wei
    Gou, Huiyang
    Piquini, Paulo Cesar
    Kang, Tae Won
    Mao, Ho-Kwang
    Ahuja, Rajeev
    KTH, Skolan för industriell teknik och management (ITM), Materialvetenskap, Tillämpad materialfysik. Uppsala University, Sweden .
    Revealing an unusual transparent phase of superhard iron tetraboride under high pressure2014Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 48, s. 17050-17053Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    First principles-based electronic structure calculations of super-hard iron tetraboride (FeB4) under high pressure have been undertaken in this study. Starting with a "conventional" superconducting phase of this material under high pressure leads to an unexpected phase transition toward a semiconducting one. This transition occurred at 53.7 GPa, and this pressure acts as a demarcation between two distinct crystal symmetries, metallic orthorhombic and semiconducting tetragonal phases, with Pnnm and I4(1)/acd space groups, respectively. In this work, the electron-phonon coupling-derived superconducting T-c has been determined up to 60 GPa and along with optical band gap variation with increasing pressure up to 300 GPa. The dynamic stability has been confirmed by phonon dispersion calculations throughout this study.

  • 50.
    Kozlov, Alexander
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Huss, Mikael
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, Sten
    Simple cellular and network control principles govern complex patterns of motor behavior2009Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 47, s. 20027-20032Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The vertebrate central nervous system is organized in modules that independently execute sophisticated tasks. Such modules are flexibly controlled and operate with a considerable degree of autonomy. One example is locomotion generated by spinal central pattern generator networks (CPGs) that shape the detailed motor output. The level of activity is controlled from brainstem locomotor command centers, which in turn, are under the control of the basal ganglia. By using a biophysically detailed, full-scale computational model of the lamprey CPG (10,000 neurons) and its brainstem/forebrain control, we demonstrate general control principles that can adapt the network to different demands. Forward or backward locomotion and steering can be flexibly controlled by local synaptic effects limited to only the very rostral part of the network. Variability in response properties within each neuronal population is an essential feature and assures a constant phase delay along the cord for different locomotor speeds.

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