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1.
  • Urbonaviciute, Vilma, et al. (författare)
  • Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis
  • 2023
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Stockholm : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:25
  • Tidskriftsartikel (refereegranskat)abstract
    • A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. It has been difficult to find safe ways to steer the targeting of natural regulatory antigen. Here, we show that the administration of exog-enous mouse major histocompatibility complex class II protein bounding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen-specific TCR through a positively charged tag. This leads to expanding a VISTA-positive nonconventional regulatory T cells, resulting in a potent dominant suppressive effect and protection against arthritis in mice. The therapeutic effect is dom-inant and tissue specific as the suppression can be transferred with regulatory T cells, which downregulate various autoimmune arthritis models including antibody-induced arthritis. Thus, the tolerogenic approach described here may be a promising dominant antigen-specific therapy for rheumatoid arthritis, and in principle, for autoimmune diseases in general.
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2.
  • Aarum, J, et al. (författare)
  • Migration and differentiation of neural precursor cells can be directed by microglia
  • 2003
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 100:26, s. 15983-15988
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent reports have supported the existence of neural stem cells in the adult mammalian CNS. Important features of such cells are self-renewal and multipotency, i.e., they can give rise to neurons, astrocytes, and oligodendrocytes and thus in principle replace lost cells in the CNS. Observations in several animal models of CNS diseases have shown that by unknown mechanisms endogenous as well as exogenous precursor cells preferentially migrate to damaged areas. Microglia are immunoreactive cells of nonneural lineage resident in the CNS. After injury to the CNS, microglia are rapidly activated and found concentrated at the sites of injury. In the present article we show, in two different assays, that soluble factors released from mouse microglial cells direct the migration of neural CNS precursor cells. We also provide evidence that microglia have the capacity to influence the differentiation of both adult and embryonic neural precursor cells toward a neuronal phenotype. Given that an invariant feature of pathological processes in CNS is the activation of microglia, these results indicate an important and unique role for microglia in directing the replacement of damaged or lost cells in the CNS.
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3.
  • Abdollahi Sani, Negar, et al. (författare)
  • All-printed diode operating at 1.6 GHz
  • 2014
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:33, s. 11943-11948
  • Tidskriftsartikel (refereegranskat)abstract
    • Printed electronics are considered for wireless electronic tags and sensors within the future Internet-of-things (IoT) concept. As a consequence of the low charge carrier mobility of present printable organic and inorganic semiconductors, the operational frequency of printed rectifiers is not high enough to enable direct communication and powering between mobile phones and printed e-tags. Here, we report an all-printed diode operating up to 1.6 GHz. The device, based on two stacked layers of Si and NbSi2 particles, is manufactured on a flexible substrate at low temperature and in ambient atmosphere. The high charge carrier mobility of the Si microparticles allows device operation to occur in the charge injection-limited regime. The asymmetry of the oxide layers in the resulting device stack leads to rectification of tunneling current. Printed diodes were combined with antennas and electrochromic displays to form an all-printed e-tag. The harvested signal from a Global System for Mobile Communications mobile phone was used to update the display. Our findings demonstrate a new communication pathway for printed electronics within IoT applications.
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4.
  • Abelein, Axel, et al. (författare)
  • Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation
  • 2015
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:17, s. 5407-5412
  • Tidskriftsartikel (refereegranskat)abstract
    • Metal ions have emerged to play a key role in the aggregation process of amyloid beta (A beta) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic A beta-Zn2+ binding features as well as how Zn2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc A beta(40) aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn2+, the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn2+ ion, forming a marginally stable, short-lived folded A beta(40) species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded A beta(40)-Zn2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for A beta(40).
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5.
  • Abraham, Nabil M., et al. (författare)
  • Pathogen-mediated manipulation of arthropod microbiota to promote infection
  • 2017
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:5, s. E781-E790
  • Tidskriftsartikel (refereegranskat)abstract
    • Arthropods transmit diverse infectious agents; however, the ways microbes influence their vector to enhance colonization are poorly understood. Ixodes scapularis ticks harbor numerous human pathogens, including Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis. We now demonstrate that A. phagocytophilum modifies the I. scapularis microbiota to more efficiently infect the tick. A. phagocytophilum induces ticks to express Ixodes scapularis antifreeze glycoprotein (iafgp), which encodes a protein with several properties, including the ability to alter bacterial biofilm formation. IAFGP thereby perturbs the tick gut microbiota, which influences the integrity of the peritrophic matrix and gut barrier-critical obstacles for Anaplasma colonization. Mechanistically, IAFGP binds the terminal D-alanine residue of the pentapeptide chain of bacterial peptidoglycan, resulting in altered permeability and the capacity of bacteria to form biofilms. These data elucidate the molecular mechanisms by which a human pathogen appropriates an arthropod antibacterial protein to alter the gut microbiota and more effectively colonize the vector.
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6.
  • Acerbi, Alberto, et al. (författare)
  • Cultural evolution and individual development of openness and conservatism
  • 2009
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:45, s. 18931-18935
  • Tidskriftsartikel (refereegranskat)abstract
    • We present a model of cultural evolution in which an individual's propensity to engage in social learning is affected by social learning itself. We assume that individuals observe cultural traits displayed by others and decide whether to copy them based on their overall preference for the displayed traits. Preferences, too, can be transmitted between individuals. Our results show that such cultural dynamics tends to produce conservative individuals, i.e., individuals who are reluctant to copy new traits. Openness to new information, however, can be maintained when individuals need significant time to acquire the cultural traits that make them effective cultural models. We show that a gradual enculturation of young individuals by many models and a larger cultural repertoire to be acquired are favorable circumstances for the long-term maintenance of openness in individuals and groups. Our results agree with data about lifetime personality change, showing that openness to new information decreases with age. Our results show that cultural remodeling of cultural transmission is a powerful force in cultural evolution, i.e., that cultural evolution can change its own dynamics
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7.
  • Achen, M G, et al. (författare)
  • Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).
  • 1998
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 95:2
  • Tidskriftsartikel (refereegranskat)abstract
    • We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.
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8.
  • Adamczyk, Andrew J., et al. (författare)
  • Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions
  • 2011
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:34, s. 14115-14120
  • Tidskriftsartikel (refereegranskat)abstract
    • The proposal that enzymatic catalysis is due to conformational fluctuations has been previously promoted by means of indirect considerations. However, recent works have focused on cases where the relevant motions have components toward distinct conformational regions, whose population could be manipulated by mutations. In particular, a recent work has claimed to provide direct experimental evidence for a dynamical contribution to catalysis in dihydrofolate reductase, where blocking a relevant conformational coordinate was related to the suppression of the motion toward the occluded conformation. The present work utilizes computer simulations to elucidate the true molecular basis for the experimentally observed effect. We start by reproducing the trend in the measured change in catalysis upon mutations (which was assumed to arise as a result of a "dynamical knockout" caused by the mutations). This analysis is performed by calculating the change in the corresponding activation barriers without the need to invoke dynamical effects. We then generate the catalytic landscape of the enzyme and demonstrate that motions in the conformational space do not help drive catalysis. We also discuss the role of flexibility and conformational dynamics in catalysis, once again demonstrating that their role is negligible and that the largest contribution to catalysis arises from electrostatic preorganization. Finally, we point out that the changes in the reaction potential surface modify the reorganization free energy (which includes entropic effects), and such changes in the surface also alter the corresponding motion. However, this motion is never the reason for catalysis, but rather simply a reflection of the shape of the reaction potential surface.
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9.
  • Adermark, Louise, 1974, et al. (författare)
  • Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step.
  • 2007
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 104:51, s. 20564-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Endocannabinoids (eCBs) mediate short- and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies have suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it is not known whether this release process occurs automatically upon eCB synthesis or whether it is regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM11 and UCM707, but did not require activation of metabotropic glutamate receptors, l-calcium channels, nitric oxide, voltage-activated Na(+) channels, or intracellular calcium. Application of the CB(1)R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB(1) receptor by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. These findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.
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10.
  • Agerberth, B, et al. (författare)
  • FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis.
  • 1995
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 92:1, s. 195-9
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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11.
  • Aguiar-Pulido, Vanessa, et al. (författare)
  • Systems biology analysis of human genomes points to key pathways conferring spina bifida risk
  • 2021
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 118:51
  • Tidskriftsartikel (refereegranskat)abstract
    • Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance, and environmental influences that hamper genome-wide association studies approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases versus controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, and essential transcriptional regulation consistent with their having impact on the pathogenesis of human SB. Additionally, an interrogation of conserved noncoding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to the interrogation of coding and noncoding sequence variant contributions to rare complex genetic disorders.
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12.
  • Aguirre Rivera, Javier, 1989-, et al. (författare)
  • Real-time measurements of aminoglycoside effects on protein synthesis in live cells
  • 2021
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:9
  • Tidskriftsartikel (refereegranskat)abstract
    • The spread of antibiotic resistance is turning many of the currently used antibiotics less effective against common infections. To address this public health challenge, it is critical to enhance our understanding of the mechanisms of action of these compounds. Aminoglycoside drugs bind the bacterial ribosome, and decades of results from in vitro biochemical and structural approaches suggest that these drugs disrupt protein synthesis by inhibiting the ribosome's translocation on the messenger RNA, as well as by inducing miscoding errors. So far, however, we have sparse information about the dynamic effects of these compounds on protein synthesis inside the cell. In the present study, we measured the effect of the aminoglycosides apramycin, gentamicin, and paromomycin on ongoing protein synthesis directly in live Escherichia coli cells by tracking the binding of dye-labeled transfer RNAs to ribosomes. Our results suggest that the drugs slow down translation elongation two- to fourfold in general, and the number of elongation cycles per initiation event seems to decrease to the same extent. Hence, our results imply that none of the drugs used in this study cause severe inhibition of translocation.
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13.
  • Ahmed, M, et al. (författare)
  • A hypothalamic pathway for Augmentor α-controlled body weight regulation
  • 2022
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:16, s. e2200476119-
  • Tidskriftsartikel (refereegranskat)abstract
    • Augmentor α and β (Augα and Augβ) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Augα functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Augα fragment and monomeric Augβ also bind to Alk and potently stimulate cellular responses. While previous studies demonstrated that oncogenic Alk mutants function as important drivers of a variety of human cancers, the physiological roles of Augα and Augβ are poorly understood. Here, we investigate the physiological roles of Augα and Augβ by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Augα single knockout and double knockout of Augα and Augβ exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Augα-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Augβ-knockout mice showed similar weight curves as the littermate controls. Experiments are presented demonstrating that Augα is robustly expressed and metabolically regulated in agouti-related peptide (AgRP) neurons, cells that control whole-body energy homeostasis in part via their projections to the paraventricular nucleus (PVN). Moreover, both Alk and melanocortin receptor-4 are expressed in discrete neuronal populations in the PVN and are regulated by projections containing Augα and AgRP, respectively, demonstrating that two distinct mechanisms that regulate pigmentation operate in the hypothalamus to control body weight. These experiments show that Alk-driven cancers were co-opted from a neuronal pathway in control of body weight, offering therapeutic opportunities for metabolic diseases and cancer.
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14.
  • Ahn, Young O., et al. (författare)
  • Conformational coupling between the active site and residues within the K-C-channel of the Vibrio cholerae cbb(3)-type (C-family) oxygen reductase
  • 2014
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:42, s. E4419-E4428
  • Tidskriftsartikel (refereegranskat)abstract
    • The respiratory chains of nearly all aerobic organisms are terminated by proton-pumping heme-copper oxygen reductases (HCOs). Previous studies have established that C-family HCOs contain a single channel for uptake from the bacterial cytoplasm of all chemical and pumped protons, and that the entrance of the K-C-channel is a conserved glutamate in subunit III. However, the majority of the K-C-channel is within subunit I, and the pathway from this conserved glutamate to subunit I is not evident. In the present study, molecular dynamics simulations were used to characterize a chain of water molecules leading from the cytoplasmic solution, passing the conserved glutamate in subunit III and extending into subunit I. Formation of the water chain, which controls the delivery of protons to the K-C-channel, was found to depend on the conformation of Y241(Vc), located in subunit I at the interface with subunit III. Mutations of Y241(Vc) (to A/F/H/S) in the Vibrio cholerae cbb(3) eliminate catalytic activity, but also cause perturbations that propagate over a 28-angstrom distance to the active site heme b(3). The data suggest a linkage between residues lining the KC-channel and the active site of the enzyme, possibly mediated by transmembrane helix alpha 7, which contains both Y241(Vc) and the active site crosslinked Y255(Vc), as well as two Cu-B histidine ligands. Other mutations of residues within or near helix alpha 7 also perturb the active site, indicating that this helix is involved in modulation of the active site of the enzyme.
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15.
  • Aizman, O., et al. (författare)
  • Ouabain, a steroid hormone that signals with slow calcium oscillations
  • 2001
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 98:23, s. 13420-13424
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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16.
  • Akkineni, Susrut, et al. (författare)
  • Amyloid-like amelogenin nanoribbons template mineralization via a low-energy interface of ion binding sites
  • 2022
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:19
  • Tidskriftsartikel (refereegranskat)abstract
    • Protein scaffolds direct the organization of amorphous precursors that transform into mineralized tissues, but the templating mechanism remains elusive. Motivated by models for the biomineralization of tooth enamel, wherein amyloid-like amelogenin nanoribbons guide the mineralization of apatite filaments, we investigated the impact of nanoribbon structure, sequence, and chemistry on amorphous calcium phosphate (ACP) nucleation. Using full-length human amelogenin and peptide analogs with an amyloid-like domain, films of β-sheet nanoribbons were self-assembled on graphite and characterized by in situ atomic force microscopy and molecular dynamics simulations. All sequences substantially reduce nucleation barriers for ACP by creating low-energy interfaces, while phosphoserines along the length of the nanoribbons dramatically enhance kinetic factors associated with ion binding. Furthermore, the distribution of negatively charged residues along the nanoribbons presents a potential match to the Ca–Ca distances of the multi-ion complexes that constitute ACP. These findings show that amyloid-like amelogenin nanoribbons provide potent scaffolds for ACP mineralization by presenting energetically and stereochemically favorable templates of calcium phosphate ion binding and suggest enhanced surface wetting toward calcium phosphates in general.
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17.
  • Akopyan, Karen, et al. (författare)
  • Translocation of surface-localized effectors in type III secretion
  • 2011
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:4, s. 1639-1644
  • Tidskriftsartikel (refereegranskat)abstract
    • Pathogenic Yersinia species suppress the host immune response by using a plasmid-encoded type III secretion system (T3SS) to translocate virulence proteins into the cytosol of the target cells. T3SS-dependent protein translocation is believed to occur in one step from the bacterial cytosol to the target-cell cytoplasm through a conduit created by the T3SS upon target cell contact. Here, we report that T3SS substrates on the surface of Yersinia pseudotuberculosis are translocated into target cells. Upon host cell contact, purified YopH coated on Y. pseudotuberculosis was specifically and rapidly translocated across the target-cell membrane, which led to a physiological response in the infected cell. In addition, translocation of externally added YopH required a functional T3SS and a specific translocation domain in the effector protein. Efficient, T3SS-dependent translocation of purified YopH added in vitro was also observed when using coated Salmonella typhimurium strains, which implies that T3SS-mediated translocation of extracellular effector proteins is conserved among T3SS-dependent pathogens. Our results demonstrate that polarized T3SS-dependent translocation of proteins can be achieved through an intermediate extracellular step that can be reconstituted in vitro. These results indicate that translocation can occur by a different mechanism from the assumed single-step conduit model.
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18.
  • Alaei-Mahabadi, Babak, et al. (författare)
  • Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers.
  • 2016
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 113:48, s. 13768-13773
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor genomes are mosaics of somatic structural variants (SVs) that may contribute to the activation of oncogenes or inactivation of tumor suppressors, for example, by altering gene copy number amplitude. However, there are multiple other ways in which SVs can modulate transcription, but the general impact of such events on tumor transcriptional output has not been systematically determined. Here we use whole-genome sequencing data to map SVs across 600 tumors and 18 cancers, and investigate the relationship between SVs, copy number alterations (CNAs), and mRNA expression. We find that 34% of CNA breakpoints can be clarified structurally and that most amplifications are due to tandem duplications. We observe frequent swapping of strong and weak promoters in the context of gene fusions, and find that this has a measurable global impact on mRNA levels. Interestingly, several long noncoding RNAs were strongly activated by this mechanism. Additionally, SVs were confirmed in telomere reverse transcriptase (TERT) upstream regions in several cancers, associated with elevated TERT mRNA levels. We also highlight high-confidence gene fusions supported by both genomic and transcriptomic evidence, including a previously undescribed paired box 8 (PAX8)-nuclear factor, erythroid 2 like 2 (NFE2L2) fusion in thyroid carcinoma. In summary, we combine SV, CNA, and expression data to provide insights into the structural basis of CNAs as well as the impact of SVs on gene expression in tumors.
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19.
  • Alava, Mikko, et al. (författare)
  • Circumspect descent prevails in solving random constraint satisfaction problems
  • 2008
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:40, s. 15253-15257
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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20.
  • Alavioon, Ghazal, et al. (författare)
  • Haploid selection within a single ejaculate increases offspring fitness
  • 2017
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; :30, s. 8053-8058
  • Tidskriftsartikel (refereegranskat)abstract
    • An inescapable consequence of sex in eukaryotes is the evolution of a biphasic life cycle with alternating diploid and haploid phases. The occurrence of selection during the haploid phase can have far-reaching consequences for fundamental evolutionary processes including the rate of adaptation, the extent of inbreeding depression, and the load of deleterious mutations, as well as for applied research into fertilization technology. Although haploid selection is well established in plants, current dogma assumes that in animals, intact fertile sperm within a single ejaculate are equivalent at siring viable offspring. Using the zebrafish Danio rerio, we show that selection on phenotypic variation among intact fertile sperm within an ejaculate affects offspring fitness. Longer-lived sperm sired embryos with increased survival and a reduced number of apoptotic cells, and adult male offspring exhibited higher fitness. The effect on embryo viability was carried over into the second generation without further selection and was equally strong in both sexes. Sperm pools selected by motile phenotypes differed genetically at numerous sites throughout the genome. Our findings clearly link within-ejaculate variation in sperm phenotype to offspring fitness and sperm genotype in a vertebrate and have major implications for adaptive evolution.
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21.
  • Albert, Heike, et al. (författare)
  • In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner
  • 2008
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 105:39, s. 15005-15009
  • Tidskriftsartikel (refereegranskat)abstract
    • IgG antibodies are potent inducers of proinflammatory responses. During autoimmune diseases such as arthritis and systemic lupus erythematosus, IgG autoantibodies are responsible for the chronic inflammation and destruction of healthy tissues by cross-linking Fc receptors on innate immune effector cells. The sugar moiety attached to the asparagine-297 residue in the constant domain of the antibody is critical for the overall structure and function of the molecule. Removal of this sugar domain leads to the loss of the proinflammatory activity, suggesting that in vivo modulation of antibody glycosylation might be a strategy to interfere with autoimmune processes. In this work, we investigated whether removal of the majority of the IgG-associated sugar domain by endoglycosidase S (EndoS) from Streptococcus pyogenes is able to interfere with autoimmune inflammation. We demonstrate that EndoS injection efficiently removes the IgG-associated sugar domain in vivo and interferes with autoantibody-mediated proinflammatory processes in a variety of autoimmune models. Importantly, however, we observed a differential impact of EndoS-mediated sugar side chain hydrolysis on IgG activity depending on the individual IgG subclass.
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22.
  • Alberts, Susan C., et al. (författare)
  • Reproductive aging patterns in primates reveal that humans are distinct
  • 2013
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:33, s. 13440-13445
  • Tidskriftsartikel (refereegranskat)abstract
    • Women rarely give birth after similar to 45 y of age, and they experience the cessation of reproductive cycles, menopause, at similar to 50 y of age after a fertility decline lasting almost two decades. Such reproductive senescence in mid-lifespan is an evolutionary puzzle of enduring interest because it should be inherently disadvantageous. Furthermore, comparative data on reproductive senescence from other primates, or indeed other mammals, remains relatively rare. Here we carried out a unique detailed comparative study of reproductive senescence in seven species of nonhuman primates in natural populations, using long-term, individual-based data, and compared them to a population of humans experiencing natural fertility and mortality. In four of seven primate species we found that reproductive senescence occurred before death only in a small minority of individuals. In three primate species we found evidence of reproductive senescence that accelerated throughout adulthood; however, its initial rate was much lower than mortality, so that relatively few individuals experienced reproductive senescence before death. In contrast, the human population showed the predicted and well-known pattern in which reproductive senescence occurred before death for many women and its rate accelerated throughout adulthood. These results provide strong support for the hypothesis that reproductive senescence in midlife, although apparent in natural-fertility, natural-mortality populations of humans, is generally absent in other primates living in such populations.
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23.
  • Alheim, K, et al. (författare)
  • Interleukin 1 expression is inducible by nerve growth factor in PC12 pheochromocytoma cells.
  • 1991
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 88:20, s. 9302-6
  • Tidskriftsartikel (refereegranskat)abstract
    • Expression of the cytokine interleukin 1 alpha (IL-1 alpha) was demonstrated in the rat PC12 pheochromocytoma cell line by (i) immunohistochemistry using rabbit polyclonal antisera raised against the recombinant murine IL-1 alpha, (ii) an ELISA, and (iii) a specific cell conversion bioassay based on the use of LBRM33-1A5 cells. IL-1 alpha mRNA was demonstrated in the PC12 cells, by PCR amplification. Constitutive expression of IL-1 alpha in PC12 cells was demonstrated in all experiments, although the cellular levels of IL-1 alpha-like immunoreactivity varied. The expression of IL-1 alpha, as studied at the mRNA level, was inducible by mouse nerve growth factor (7S NGF), and the gene product level was inducible in a dose- and time-dependent fashion by 7S NGF. The maximum induction corresponds to a 600% increase in IL-1 alpha-like immunoreactivity above the expression level found in noninduced cells and occurred after a 3-day incubation of the cells with NGF at 0.75 micrograms/ml of culture medium. The significance of the ability of NGF to induce IL-1 expression lies in the fact that IL-1 itself also acts as a growth factor that promotes glial proliferation and, even more importantly, IL-1 itself induces the expression of NGF at peripheral nerve injury [Lindholm, D., Heumann, R., Meyer, M. & Thoenen, H. (1987) Nature (London) 330, 658-659].
  •  
24.
  • Ali, Muhammad Akhtar, et al. (författare)
  • Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells
  • 2015
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:25, s. 7743-7748
  • Tidskriftsartikel (refereegranskat)abstract
    • The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.
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25.
  • Alimohammadi, Mohammad, et al. (författare)
  • Pulmonary Autoimmunity as a Feature of Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial Autoantigen
  • 2009
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:11, s. 4396-4401
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.
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26.
  • Alkasalias, T, et al. (författare)
  • Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent
  • 2014
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 111:48, s. 17188-17193
  • Tidskriftsartikel (refereegranskat)abstract
    • Normal microenvironments can restrict cancer development and progression. Inhibition of tumor cell growth and motility by normal fibroblasts is one measurable manifestation of this multicomponential control. Here we show that inhibition withstands formalin fixation and can be augmented by the addition of conditioned medium derived from live cultures of tumor cells confronting the stromal fibroblasts. We describe a number of molecules involved in this process. This study lays the foundation for further mechanistic studies of this important phenomenon and its contribution to possible dormancy and the tumor’s resistance to therapy.
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27.
  • Alkasalias, Twana, et al. (författare)
  • RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo
  • 2017
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:8, s. E1413-E1421
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  •  
28.
  • Allan, Eric, et al. (författare)
  • Interannual variation in land-use intensity enhances grassland multidiversity
  • 2014
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:1, s. 308-313
  • Tidskriftsartikel (refereegranskat)abstract
    • Although temporal heterogeneity is a well-accepted driver of biodiversity, effects of interannual variation in land-use intensity (LUI) have not been addressed yet. Additionally, responses to land use can differ greatly among different organisms; therefore, overall effects of land-use on total local biodiversity are hardly known. To test for effects of LUI (quantified as the combined intensity of fertilization, grazing, and mowing) and interannual variation in LUI (SD in LUI across time), we introduce a unique measure of whole-ecosystem biodiversity, multidiversity. This synthesizes individual diversity measures across up to 49 taxonomic groups of plants, animals, fungi, and bacteria from 150 grasslands. Multidiversity declined with increasing LUI among grasslands, particularly for rarer species and aboveground organisms, whereas common species and belowground groups were less sensitive. However, a high level of interannual variation in LUI increased overall multidiversity at low LUI and was even more beneficial for rarer species because it slowed the rate at which the multidiversity of rare species declined with increasing LUI. In more intensively managed grasslands, the diversity of rarer species was, on average, 18% of the maximum diversity across all grasslands when LUI was static over time but increased to 31% of the maximum when LUI changed maximally over time. In addition to decreasing overall LUI, we suggest varying LUI across years as a complementary strategy to promote biodiversity conservation.
  •  
29.
  • Allander, T, et al. (författare)
  • Cloning of a human parvovirus by molecular screening of respiratory tract samples
  • 2005
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 102:36, s. 12891-12896
  • Tidskriftsartikel (refereegranskat)abstract
    • The identification of new virus species is a key issue for the study of infectious disease but is technically very difficult. We developed a system for large-scale molecular virus screening of clinical samples based on host DNA depletion, random PCR amplification, large-scale sequencing, and bioinformatics. The technology was applied to pooled human respiratory tract samples. The first experiments detected seven human virus species without the use of any specific reagent. Among the detected viruses were one coronavirus and one parvovirus, both of which were at that time uncharacterized. The parvovirus, provisionally named human bocavirus, was in a retrospective clinical study detected in 17 additional patients and associated with lower respiratory tract infections in children. The molecular virus screening procedure provides a general culture-independent solution to the problem of detecting unknown virus species in single or pooled samples. We suggest that a systematic exploration of the viruses that infect humans, “the human virome,” can be initiated.
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30.
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31.
  • Allen, LT, et al. (författare)
  • Interaction of soft condensed materials with living cells: Phenotype/transcriptome correlations for the hydrophobic effect
  • 2003
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 100, s. 6331-6336
  • Tidskriftsartikel (refereegranskat)abstract
    • The assessment of biomaterial compatibility relies heavily on the analysis of macroscopic cellular responses to material interaction. However, new technologies have become available that permit a more profound understanding of the molecular basis of cell-biomaterial interaction. Here, both conventional phenotypic and contemporary transcriptomic (DNA microarray-based) analysis techniques were combined to examine the interaction of cells with a homologous series of copolymer films that subtly vary in terms of surface hydrophobicity. More specifically, we used differing combinations of N-isopropylacrylamide, which is presently used as an adaptive cell culture substrate, and the more hydrophobic, yet structurally similar, monomer N-tert-butylacrylamide. We show here that even discrete modifications with respect to the physiochemistry of soft amorphous materials can lead to significant impacts on the phenotype of interacting cells. Furthermore, we have elucidated putative links between phenotypic responses to cell-biomaterial interaction and global gene expression profile alterations. This case study indicates that high-throughput analysis of gene expression not only can greatly refine our knowledge of cell-biomaterial interaction, but also can yield novel biomarkers for potential use in biocompatibility assessment
  •  
32.
  • Allgardsson, Anders, et al. (författare)
  • Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6
  • 2016
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:20, s. 5514-5519
  • Tidskriftsartikel (refereegranskat)abstract
    • Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.
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33.
  • Almaca, J, et al. (författare)
  • Young capillary vessels rejuvenate aged pancreatic islets
  • 2014
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 111:49, s. 17612-17617
  • Tidskriftsartikel (refereegranskat)abstract
    • The regulation of blood glucose is a homeostatic process that declines with age, but it is unknown whether this disturbance is a consequence of intrinsic dysfunction of the regulatory organ, the pancreatic islet. In marked contrast to the widely held notion that the insulin-producing pancreatic beta cell loses function with wear and tear, and thus causes age-related disturbances in glucose homeostasis, we show that mouse and human beta cells are fully functional at advanced age. The pancreatic islet as an organ, however, is threatened by vascular senescence. Replacing the islet vasculature in aged islet grafts rejuvenates the islet and fully restores glucose homeostasis, indicating that islet blood vessels should be targeted to mitigate frail glucose homeostasis associated with aging.
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34.
  • Almås, Ingvild, et al. (författare)
  • Global evidence on the selfish rich inequality hypothesis
  • 2022
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:3
  • Tidskriftsartikel (refereegranskat)abstract
    • We report on a study of whether people believe that the rich are richer than the poor because they have been more selfish in life, using data from more than 26,000 individuals in 60 countries. The findings show a strong belief in the selfish rich inequality hypothesis at the global level; in the majority of countries, the mode is to strongly agree with it. However, we also identify important between- and within-country variation. We find that the belief in selfish rich inequality is much stronger in countries with extensive corruption and weak institutions and less strong among people who are higher in the income distribution in their society. Finally, we show that the belief in selfish rich inequality is predictive of people’s policy views on inequality and redistribution: It is significantly positively associated with agreeing that inequality in their country is unfair, and it is significantly positively associated with agreeing that the government should aim to reduce inequality. These relationships are highly significant both across and within countries and robust to including country-level or individual-level controls and using Lasso-selected regressors. Thus, the data provide compelling evidence of people believing that the rich are richer because they have been more selfish in life and perceiving selfish behavior as creating unfair inequality and justifying equalizing policies.
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35.
  • Alonso-Mori, Roberto, et al. (författare)
  • Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode
  • 2012
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:47, s. 19103-19107
  • Tidskriftsartikel (refereegranskat)abstract
    • The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this probe-before-destroy approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. K beta(1,3) XES spectra of Mn-II and Mn-2(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to > 100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.
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36.
  • Alonso-Sáez, Laura, et al. (författare)
  • Role for urea in nitrification by polar marine Archaea
  • 2012
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:44, s. 17989-17994
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite the high abundance of Archaea in the global ocean, their metabolism and biogeochemical roles remain largely unresolved. We investigated the population dynamics and metabolic activity of Thaumarchaeota in polar environments, where these microorganisms are particularly abundant and exhibit seasonal growth. Thaumarchaeota were more abundant in deep Arctic and Antarctic waters and grew throughout the winter at surface and deeper Arctic halocline waters. However, in situ single-cell activity measurements revealed a low activity of this group in the uptake of both leucine and bicarbonate (<5% Thaumarchaeota cells active), which is inconsistent with known heterotrophic and autotrophic thaumarchaeal lifestyles. These results suggested the existence of alternative sources of carbon and energy. Our analysis of an environmental metagenome from the Arctic winter revealed that Thaumarchaeota had pathways for ammonia oxidation and, unexpectedly, an abundance of genes involved in urea transport and degradation. Quantitative PCR analysis confirmed that most polar Thaumarchaeota had the potential to oxidize ammonia, and a large fraction of them had urease genes, enabling the use of urea to fuel nitrification. Thaumarchaeota from Arctic deep waters had a higher abundance of urease genes than those near the surface suggesting genetic differences between closely related archaeal populations. In situ measurements of urea uptake and concentration in Arctic waters showed that small-sized prokaryotes incorporated the carbon from urea, and the availability of urea was often higher than that of ammonium. Therefore, the degradation of urea may be a relevant pathway for Thaumarchaeota and other microorganisms exposed to the low-energy conditions of dark polar waters.
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37.
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38.
  • Alsmark, Cecilia M., et al. (författare)
  • The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae
  • 2004
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 101:26, s. 9716-9721
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the complete genomes of two human pathogens, Bartonella quintana (1,581,384 bp) and Bartonella henselae (1,931,047 bp). The two pathogens maintain several similarities in being transmitted by insect vectors, using mammalian reservoirs, infecting similar cell types (endothelial cells and erythrocytes) and causing vasculoproliferative changes in immunocompromised hosts. A primary difference between the two pathogens is their reservoir ecology. Whereas B. quintana is a specialist, using only the human as a reservoir, B. henselae is more promiscuous and is frequently isolated from both cats and humans. Genome comparison elucidated a high degree of overall similarity with major differences being B. henselae specific genomic islands coding for filamentous hemagglutinin, and evidence of extensive genome reduction in B. quintana, reminiscent of that found in Rickettsia prowazekii. Both genomes are reduced versions of chromosome I from the highly related pathogen Brucella melitensis. Flanked by two rRNA operons is a segment with similarity to genes located on chromosome II of B. melitensis, suggesting that it was acquired by integration of megareplicon DNA in a common ancestor of the two Bartonella species. Comparisons of the vector-host ecology of these organisms suggest that the utilization of host-restricted vectors is associated with accelerated rates of genome degradation and may explain why human pathogens transmitted by specialist vectors are outnumbered by zoonotic agents, which use vectors of broad host ranges.
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39.
  • Alsterberg, Christian, 1982, et al. (författare)
  • Consumers mediate the effects of experimental ocean acidification and warming on primary producers.
  • 2013
  • Ingår i: Proceedings of the National Academy of Science of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:21, s. 8603-8608
  • Tidskriftsartikel (refereegranskat)abstract
    • It is well known that ocean acidification can have profound impacts on marine organisms. However, we know little about the direct and indirect effects of ocean acidification and also how these effects interact with other features of environmental change such as warming and declining consumer pressure. In this study, we tested whether the presence of consumers (invertebrate mesograzers) influenced the interactive effects of ocean acidification and warming on benthic microalgae in a seagrass community mesocosm experiment. Net effects of acidification and warming on benthic microalgal biomass and production, as assessed by analysis of variance, were relatively weak regardless of grazer presence. However, partitioning these net effects into direct and indirect effects using structural equation modeling revealed several strong relationships. In the absence of grazers, benthic microalgae were negatively and indirectly affected by sediment-associated microalgal grazers and macroalgal shading, but directly and positively affected by acidification and warming. Combining indirect and direct effects yielded no or weak net effects. In the presence of grazers, almost all direct and indirect climate effects were nonsignificant. Our analyses highlight that (i) indirect effects of climate change may be at least as strong as direct effects, (ii) grazers are crucial in mediating these effects, and (iii) effects of ocean acidification may be apparent only through indirect effects and in combination with other variables (e.g., warming). These findings highlight the importance of experimental designs and statistical analyses that allow us to separate and quantify the direct and indirect effects of multiple climate variables on natural communities.
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40.
  • Altmejd, Adam, et al. (författare)
  • Inequality and COVID-19 in Sweden : Relative risks of nine bad life events, by four social gradients, in pandemic vs. prepandemic years
  • 2023
  • Ingår i: Proceedings of the National Academy of Sciences - PNAS. - : National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 120:46
  • Tidskriftsartikel (refereegranskat)abstract
    • The COVID-19 pandemic struck societies directly and indirectly, not just challenging population health but disrupting many aspects of life. Different effects of the spreading virus—and the measures to fight it—are reported and discussed in different scientific fora, with hard-to-compare methods and metrics from different traditions. While the pandemic struck some groups more than others, it is difficult to assess the comprehensive impact on social inequalities. This paper gauges social inequalities using individual-level administrative data for Sweden’s entire population. We describe and analyze the relative risks for different social groups in four dimensions—gender, education, income, and world region of birth—to experience three types of COVID-19 incidence, as well as six additional negative life outcomes that reflect general health, access to medical care, and economic strain. During the pandemic, the overall population faced severe morbidity and mortality from COVID-19 and saw higher all-cause mortality, income losses and unemployment risks, as well as reduced access to medical care. These burdens fell more heavily on individuals with low income or education and on immigrants. Although these vulnerable groups experienced larger absolute risks of suffering the direct and indirect consequences of the pandemic, the relative risks in pandemic years (2020 and 2021) were conspicuously similar to those in prepandemic years (2016 to 2019).
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41.
  • Ambati, Aditya, et al. (författare)
  • Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci
  • 2021
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 x 10(-9)) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R-2 = 0.15; P < 2.0 x 10(-22) at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.
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42.
  • Ambikan, Anoop T., et al. (författare)
  • Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection
  • 2023
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:37
  • Tidskriftsartikel (refereegranskat)abstract
    • Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.
  •  
43.
  • Ambort, Daniel, 1978, et al. (författare)
  • Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin.
  • 2012
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 109:15, s. 5645-50
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 Ca(2+) 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. The MUC2-N aggregates were dissolved by removing Ca(2+) 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.
  •  
44.
  • Anand, S, et al. (författare)
  • Divergence of Hoxc8 early enhancer parallels diverged axial morphologies between mammals and fishes
  • 2003
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 100:26, s. 15666-15669
  • Tidskriftsartikel (refereegranskat)abstract
    • There is considerable interest in understanding how cis-regulatory modifications drive morphological changes across species. Because developmental regulatory genes, including Hox genes, are remarkably conserved, their noncoding regulatory regions are likely sources for variations. Modifications of Hox cis-regulatory elements have potential to alter Hox gene expression and, hence, axial morphologies. In vertebrates, differences in the axial levels of Hox gene expression correlate with differences in the number and relative position of thoracic vertebrae. Variation in cis-regulatory elements of Hox genes can be identified by comparative sequence and reporter gene analyses in transgenic mouse embryos. Using these approaches, we show a remarkable divergence of the Hoxc8 early enhancers between mammals and fishes representing diverse axial morphologies. Extensive restructuring of the Hoxc8 early enhancer including nucleotide substitutions, inversion, and divergence result in distinct patterns of reporter gene expression along the embryonic axis. Our results provide an evolutionary perspective on how the enhancer elements are engineered and support the hypothesis that remodeling of Hox regulatory elements in different species has played a significant role in generating morphological diversity.
  •  
45.
  • Anckarsäter, Henrik, 1966 (författare)
  • Has biology disproved free will and moral responsibility?
  • 2010
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 107:28 in process
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
  •  
46.
  • Anderson, Peter (författare)
  • Brief predator sound exposure elicits behavioral and neuronal long-term sensitization in the olfactory system of an insect
  • 2011
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 108, s. 3401-3405
  • Tidskriftsartikel (refereegranskat)abstract
    • Modulation of sensitivity to sensory cues by experience is essential for animals to adapt to a changing environment. Sensitization and adaptation to signals of the same modality as a function of experience have been shown in many cases, and some of the neurobiological mechanisms underlying these processes have been described. However, the influence of sensory signals on the sensitivity of a different modality is largely unknown. In males of the noctuid moth, Spodoptera littoralis, the sensitivity to the female-produced sex pheromone increases 24 h after a brief preexposure with pheromone at the behavioral and central nervous level. Here we show that this effect is not confined to the same sensory modality: the sensitivity of olfactory neurons can also be modulated by exposure to a different sensory stimulus, i.e., a pulsed stimulus mimicking echolocating sounds from attacking insectivorous bats. We tested responses of preexposed male moths in a walking bioassay and recorded from neurons in the primary olfactory center, the antennal lobe. We show that brief exposure to a bat call, but not to a behaviorally irrelevant tone, increases the behavioral sensitivity of male moths to sex pheromone 24 h later in the same way as exposure to the sex pheromone itself. The observed behavioral modification is accompanied by an increase in the sensitivity of olfactory neurons in the antennal lobe. Our data provide thus evidence for cross-modal experience-dependent plasticity not only on the behavioral level, but also on the central nervous level, in an insect.
  •  
47.
  • Andersson, Charlotta S, et al. (författare)
  • A Mycobacterium tuberculosis ligand-binding Mn/Fe protein reveals a new cofactor in a remodeled R2-protein scaffold
  • 2009
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:14, s. 5633-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Chlamydia trachomatis R2c is the prototype for a recently discovered group of ribonucleotide reductase R2 proteins that use a heterodinuclear Mn/Fe redox cofactor for radical generation and storage. Here, we show that the Mycobacterium tuberculosis protein Rv0233, an R2 homologue and a potential virulence factor, contains the heterodinuclear manganese/iron-carboxylate cofactor but displays a drastic remodeling of the R2 protein scaffold into a ligand-binding oxidase. The first structural characterization of the heterodinuclear cofactor shows that the site is highly specific for manganese and iron in their respective positions despite a symmetric arrangement of coordinating residues. In this protein scaffold, the Mn/Fe cofactor supports potent 2-electron oxidations as revealed by an unprecedented tyrosine-valine crosslink in the active site. This wolf in sheep's clothing defines a distinct functional group among R2 homologues and may represent a structural and functional counterpart of the evolutionary ancestor of R2s and bacterial multicomponent monooxygenases.
  •  
48.
  • Andersson, David A., et al. (författare)
  • Optimization of ionic conductivity in doped ceria
  • 2006
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 103:10, s. 3518-3521
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  •  
49.
  • Andersson, Dan I. (författare)
  • Evolving promiscuously
  • 2011
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:4, s. 1199-1200
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
  •  
50.
  • Andersson, Dan I, et al. (författare)
  • Muller's ratchet decreases fitness of a DNA-based microbe
  • 1996
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 93:2, s. 906-907
  • Tidskriftsartikel (refereegranskat)abstract
    • Muller proposed that an asexual organism will inevitably accumulate deleterious mutations, resulting in an increase of the mutational load and an inexorable, ratchet-like, loss of the least mutated class [Muller, H.J. (1964) Mutat. Res. 1, 2-9]. The operation of Muller's ratchet on real populations has been experimentally demonstrated only in RNA viruses. However, these cases are exceptional in that the mutation rates of the RNA viruses are extremely high. We have examined whether Muller's ratchet operates in Salmonella typhimurium, a DNA-based organism with a more typical genomic mutation rate. Cells were grown asexually under conditions expected to result in high genetic drift, and the increase in mutational load was determined. S. typhimurium accumulated mutations under these conditions such that after 1700 generations, 1% of the 444 lineages tested had suffered an obvious loss of fitness, as determined by decreased growth rate. These results suggest that in the absence of sex and with high genetic drift, genetic mechanisms, such as back or compensatory mutations, cannot compensate for the accumulation of deleterious mutations. In addition, we measured the appearance of auxotrophs, which allowed us to calculate an average spontaneous mutation rate of approximately 0.3-1.5 x 10(-9) mutations per base pair per generation. This rate is measured for the largest genetic target studied so far, a collection of about 200 genes.
  •  
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