209 results on '"Fredrik Almqvist"'
Search Results
2. Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
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Taylor M. Nye, Hasan Tükenmez, Pardeep Singh, Ana L. Flores-Mireles, Chloe L. P. Obernuefemann, Jerome S. Pinkner, Souvik Sarkar, Mari Bonde, Anders E. G. Lindgren, Karen W. Dodson, Jörgen Johansson, Fredrik Almqvist, Michael G. Caparon, and Scott J. Hultgren
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antibiotic resistance ,Multidisciplinary ,Pyridones ,VRE ,Microbial Sensitivity Tests ,N-Acetylmuramoyl-L-alanine Amidase ,Gram-Positive Bacteria ,Anti-Bacterial Agents ,Vancomycin-Resistant Enterococci ,Microbiology in the medical area ,multidrug-resistant pathogens ,Vancomycin ,Drug Resistance, Multiple, Bacterial ,Mikrobiologi inom det medicinska området ,antibiotic synergy - Abstract
The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.
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- 2022
3. An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry
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Souvik Sarkar, Andreas Larsson, Pardeep Singh, Andrew G. Cairns, and Fredrik Almqvist
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Organisk kemi ,Chemistry ,Heterocycle ,Thiazolo ,Organic Chemistry ,Flow chemistry ,Pyridone ,Ring (chemistry) ,Acyl ketene ,Combinatorial chemistry ,Design of experiments - Abstract
Thiazolino ring fused 2-pyridones are a valuable scaffold with varied and substitution dependent biological activity, accessed primarily by an acyl ketene-imine cycloaddition and rearrangement. Although powerful, some aspects of this chemistry such as the requirement for excess starting material and the production of gas can make larger scale synthesis challenging. Here we describe the development, application and scaling of a continuous flow process allowing larger scale synthesis, with better handling of hazards and more reliable scaling. Optimisation and control of conditions allows for a more efficient synthesis, with a lower equivalence of the acyl ketene precursor required.
- Published
- 2021
4. Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β Fibrils
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Jörgen Ådén, Pardeep Singh, Mohit Tyagi, Sanduni Wasana Jayaweera, Anders Olofsson, Adrian Deuschmann, Fredrik Almqvist, Anna L. Gharibyan, Anders E. G. Lindgren, and Dan E. Adolfsson
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Amyloid ,Pyridones ,Peptidomimetic ,Stereochemistry ,Nanofibers ,Peptides and proteins ,010402 general chemistry ,Fibril ,01 natural sciences ,2-Pyridone ,chemistry.chemical_compound ,mental disorders ,Organisk kemi ,Amyloid beta-Peptides ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Note ,Alkyls ,0104 chemical sciences ,Mixtures ,Intramolecular force ,Functional group ,alpha-Synuclein ,Nitro ,Povarov reaction ,Column chromatography - Abstract
A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group. Previously included in thesis in manuscript form.
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- 2020
5. K
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Jaideep B, Bharate, Jörgen, Ådén, Anna, Gharibyan, Dan E, Adolfsson, Sanduni Wasana, Jayaweera, Pardeep, Singh, Katarina, Vielfort, Mohit, Tyagi, Mari, Bonde, Sven, Bergström, Anders, Olofsson, and Fredrik, Almqvist
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Aldehydes - Abstract
We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones
- Published
- 2021
6. A novel reconstructive approach of the lumbar vertebral column from 2D MRI to 3D models
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Nerissa Naidoo, Raeesa Khan, Taiceer Abdulwahab, Karl Fredrik Almqvist, Jeyaseelan Lakshmanan, and Ivan James Prithishkumar
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Anatomy - Published
- 2022
7. Selected applications of Meldrum's acid - a tutorial
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Fredrik Almqvist, Carsten Bolm, Felix Brosge, and Pardeep Singh
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010405 organic chemistry ,Chemistry ,Organic Chemistry ,010402 general chemistry ,Meldrum's acid ,01 natural sciences ,Biochemistry ,Chemical synthesis ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,Acylation ,Electrophilic substitution ,chemistry.chemical_compound ,Nucleophile ,Graduate students ,Molecule ,Physical and Theoretical Chemistry - Abstract
Due to its unique structure and the vast array of substituents that can be attached to its core, Meldrum's acid is a molecule with exceptional chemical properties. In water, it has a remarkably low pKa value of about 4.9. Its C5 position is readily involved in electrophilic substitution reactions whereas the C4 and C6 positions are easily attacked by nucleophiles. At elevated temperatures Meldrum's acid undergoes distinctive decomposition pathways, which can be used in cycloaddition and acylation reactions. In this Tutorial Review, the authors intend to introduce the principles of the synthetic chemistry of Meldrum's acid and provide the essential knowledge for the design and preparation of compounds with desired properties. As there are many reviews focusing on a specific detail of Meldrum's acid chemistry, we would like to give a broader picture of this diverse molecule for undergraduate and graduate students as well as experienced lab leaders. For achieving this goal, some recent advances in using Meldrum's acid derivatives in synthetic scenarios are presented with the hope to further stimulate and promote research leading to additional innovative applications of this synthetically highly relevant molecule.
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- 2021
8. Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones
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Pardeep Singh, Jörgen Ådén, Dan E. Adolfsson, Andrew G. Cairns, Fredrik Almqvist, and Uwe Sauer
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Bicyclic molecule ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,Aryne ,0104 chemical sciences ,Polymer chemistry ,Surface modification ,Reactivity (chemistry) ,Physical and Theoretical Chemistry - Abstract
We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and su ...
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- 2019
9. Viral mimetic priming enhances α-synuclein-induced degeneration: Implications for Parkinson’s disease
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Andrew G. Cairns, Jörgen Ådén, Niamh Moriarty, Silvia Cabre, Laura K. Olsen, Fredrik Almqvist, Verónica Alamilla, Declan P. McKernan, and Eilís Dowd
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Male ,0301 basic medicine ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Neuroimmunomodulation ,viruses ,Genetic Vectors ,Immunology ,Priming (immunology) ,Disease ,Degeneration (medical) ,Motor Activity ,Protein Aggregation, Pathological ,Viral infection ,Rats, Sprague-Dawley ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Biomimetic Materials ,medicine ,Animals ,Gliosis ,Neuroinflammation ,Neurons ,Endocrine and Autonomic Systems ,business.industry ,Neurodegeneration ,Neurodegenerative Diseases ,Parkinson Disease ,Dependovirus ,medicine.disease ,Corpus Striatum ,Rats ,3. Good health ,Substantia Nigra ,Disease Models, Animal ,Poly I-C ,030104 developmental biology ,alpha-Synuclein ,α synuclein ,business ,030217 neurology & neurosurgery - Abstract
Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson's disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson's disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson's disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p 0.001) and astrocytosis (p 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p 0.05); and precipitated a significant impairment in forelimb kinesis (p 0.01) and sensorimotor integration (p 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson's disease.
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- 2019
10. Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
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Martina Kulén, Christer Larsson, Fredrik Almqvist, K. Syam Krishnan, Erik Chorell, James A. D. Good, Mette R. Hansen, Gregory A. Harrison, Dennis X. Zhu, Jonathan Livny, Scott J. Hultgren, Kelly Flentie, Christina L. Stallings, Anders E. G. Lindgren, Leslie A. Weiss, Torbjörn Wixe, Hasan Tükenmez, Andrew G. Cairns, Christoffer Bengtsson, Souvik Sarkar, Samantha D. Solomon, Miranda E. Schene, and Rachel L. Kinsella
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0301 basic medicine ,Multidisciplinary ,Tuberculosis ,medicine.drug_class ,030106 microbiology ,Antibiotics ,Isoniazid ,Drug resistance ,biochemical phenomena, metabolism, and nutrition ,respiratory system ,Biology ,bacterial infections and mycoses ,biology.organism_classification ,medicine.disease ,Microbiology ,Mycobacterium tuberculosis ,03 medical and health sciences ,030104 developmental biology ,Antibiotic resistance ,Drug tolerance ,medicine ,Pathogen ,medicine.drug - Abstract
Mycobacterium tuberculosis ( Mtb ) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb , we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.
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- 2019
11. Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding
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Pardeep Singh, Christian Bartens, Anders Olofsson, Kristoffer Brännström, Dan E. Adolfsson, Andrew G. Cairns, Jörgen Ådén, and Fredrik Almqvist
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chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Substrate (chemistry) ,010402 general chemistry ,Amyloid fibril ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Bridged Bicyclo Compounds ,Pyridine ,Structure–activity relationship ,Surface modification ,Tricyclic - Abstract
We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of ...
- Published
- 2019
12. A 2-Pyridone Amide Inhibitor of Transcriptional Activity in Chlamydia trachomatis
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Jim Silver, Haitham Elbir, Katarina Vielfort, Fredrik Almqvist, Carlos Núñez-Otero, Pardeep Singh, Wael Bahnan, Sven Bergström, and Åsa Gylfe
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Pharmacology ,0303 health sciences ,Transcriptional activity ,030306 microbiology ,business.industry ,Treatment options ,Eye infection ,medicine.disease_cause ,Microbiology ,03 medical and health sciences ,Infectious Diseases ,medicine ,Intracellular bacterium ,Pharmacology (medical) ,Chlamydia trachomatis ,business ,Mechanisms of Action: Physiological Effects ,030304 developmental biology - Abstract
Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to lifelong sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-Pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first-generation compound KSK120 inhibits the developmental cycle of Chlamydia, resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis, and the effect was only observable upon reinfection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen Chlamydia muridarum and in Chlamydia caviae. The molecular target of KSK213 may thus be different in C. trachomatis or nonessential in C. muridarum and C. caviae. Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNase III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-Pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.
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- 2021
13. Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes
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Ingeborg van der Lingen, Afshan Begum, Marie Lindgren, Fredrik Almqvist, Christin Grundström, Kristoffer Brännström, Andrew G. Cairns, Jörgen Johansson, Uwe Sauer, Sabine Hansen, Michael N. Hall, Martina Kulén, and A. Elisabeth Sauer-Eriksson
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Models, Molecular ,0301 basic medicine ,Protein Conformation ,Regulator ,Virulence ,Chick Embryo ,medicine.disease_cause ,DNA-binding protein ,Virulence factor ,Microbiology ,03 medical and health sciences ,Bacterial Proteins ,Listeria monocytogenes ,Drug Discovery ,medicine ,Transcriptional regulation ,Animals ,Binding site ,Pathogen ,Chemistry ,Anti-Bacterial Agents ,3. Good health ,030104 developmental biology ,Drug Design ,Molecular Medicine ,Peptide Termination Factors - Abstract
Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure-guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein “tunnel” as the main inhibitor binding site (AI), where the compounds participate in an extensive hydrophobic network that restricts the protein’s ability to form functional DNA-binding helix–turn–helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-AI selective PrfA inhibitors with potent antivirulence properties.
- Published
- 2018
14. Inhibition of curli assembly and Escherichia coli biofilm formation by the human systemic amyloid precursor transthyretin
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Xinyi Li, Kanna Nagamatsu, Joel N. Buxbaum, Fredrik Almqvist, Matthew George Chapman, Jörgen Ådén, Magdalena I. Ivanova, Brennan McMichael, Margery L. Evans, and Neha Jain
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0301 basic medicine ,endocrine system ,Multidisciplinary ,030102 biochemistry & molecular biology ,biology ,Amyloid ,Biofilm ,nutritional and metabolic diseases ,medicine.disease_cause ,biology.organism_classification ,Enterobacteriaceae ,In vitro ,03 medical and health sciences ,Transthyretin ,030104 developmental biology ,Biochemistry ,biology.protein ,medicine ,Amyloid precursor protein ,Curli assembly ,Escherichia coli - Abstract
During biofilm formation, Escherichia coli and other Enterobacteriaceae produce an extracellular matrix consisting of curli amyloid fibers and cellulose. The precursor of curli fibers is the amyloidogenic protein CsgA. The human systemic amyloid precursor protein transthyretin (TTR) is known to inhibit amyloid-β (Aβ) aggregation in vitro and suppress the Alzheimer’s-like phenotypes in a transgenic mouse model of Aβ deposition. We hypothesized that TTR might have broad antiamyloid activity because the biophysical properties of amyloids are largely conserved across species and kingdoms. Here, we report that both human WT tetrameric TTR (WT-TTR) and its engineered nontetramer-forming monomer (M-TTR, F87M/L110M) inhibit CsgA amyloid formation in vitro, with M-TTR being the more efficient inhibitor. Preincubation of WT-TTR with small molecules that occupy the T4 binding site eliminated the inhibitory capacity of the tetramer; however, they did not significantly compromise the ability of M-TTR to inhibit CsgA amyloidogenesis. TTR also inhibited amyloid-dependent biofilm formation in two different bacterial species with no apparent bactericidal or bacteriostatic effects. These discoveries suggest that TTR is an effective antibiofilm agent that could potentiate antibiotic efficacy in infections associated with significant biofilm formation.
- Published
- 2017
15. Organic Polymeric Resins Embedded with Pd NPs: Newly Designed, Efficient and Chemoselective Catalyst for Reduction of Nitrobenzenes
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Basudeb Basu, Fredrik Almqvist, Samir Kundu, Knut Irgum, Emil Byström, and Susmita Paul
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inorganic chemicals ,Organic polymer ,Materials science ,Organic Chemistry ,Inorganic chemistry ,technology, industry, and agriculture ,Palladium nanoparticles ,respiratory system ,Heterogeneous catalysis ,Catalysis ,Analytical Chemistry ,Nitrobenzene ,chemistry.chemical_compound ,chemistry ,Chemical engineering ,Organic reaction ,mental disorders ,health care economics and organizations - Abstract
Background: Organic polymer supported palladium nanoparticles (NPs) are important for use as heterogeneous catalyst in various organic reactions. This works describes Pd Nps immobilized on to polys ...
- Published
- 2016
16. Synthesis of Densely Functionalized
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Pardeep, Singh, Andrew G, Cairns, Dan E, Adolfsson, Jörgen, Ådén, Uwe H, Sauer, and Fredrik, Almqvist
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Thiazoles ,Cycloaddition Reaction ,Molecular Structure ,Pyridones ,Benzene Derivatives - Abstract
We report the synthesis of 6-arylthio-substituted
- Published
- 2019
17. Durch sichtbares Licht vermittelte Synthese von β‐Chlorketonen aus Arylcyclopropanen
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Pardeep Singh, Daniel Petzold, Burkhard König, and Fredrik Almqvist
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Chemistry ,General Medicine - Published
- 2019
18. Chemical disarming of isoniazid resistance in
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Kelly, Flentie, Gregory A, Harrison, Hasan, Tükenmez, Jonathan, Livny, James A D, Good, Souvik, Sarkar, Dennis X, Zhu, Rachel L, Kinsella, Leslie A, Weiss, Samantha D, Solomon, Miranda E, Schene, Mette R, Hansen, Andrew G, Cairns, Martina, Kulén, Torbjörn, Wixe, Anders E G, Lindgren, Erik, Chorell, Christoffer, Bengtsson, K Syam, Krishnan, Scott J, Hultgren, Christer, Larsson, Fredrik, Almqvist, and Christina L, Stallings
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Drug Resistance, Bacterial ,Antitubercular Agents ,Drug Evaluation, Preclinical ,Isoniazid ,Mycobacterium tuberculosis - Published
- 2019
19. Pyridine-Fused 2-Pyridones via Povarov and A
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Pardeep, Singh, Dan E, Adolfsson, Jörgen, Ådén, Andrew G, Cairns, Christian, Bartens, Kristoffer, Brännström, Anders, Olofsson, and Fredrik, Almqvist
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Amyloid ,Structure-Activity Relationship ,Pyridines ,Pyridones ,Bridged Bicyclo Compounds, Heterocyclic ,Heterocyclic Compounds, Bridged-Ring ,Styrenes - Abstract
We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.
- Published
- 2019
20. Visible-Light-Mediated Synthesis of β-Chloro Ketones from Aryl Cyclopropanes
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Pardeep Singh, Fredrik Almqvist, Burkhard König, and Daniel Petzold
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010405 organic chemistry ,Aryl ,chemistry.chemical_element ,Hydrochloric acid ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Oxygen ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Nitric acid ,heterocyclic compounds ,Visible spectrum - Abstract
We report the visible-light-mediated synthesis of β-chloro ketones from aryl cyclopropanes, oxygen, hydrochloric acid, and nitric acid. The operationally simple and catalyst-free method uses cheap standard laboratory reagents and displays broad functional-group tolerance. Moreover, scale up of the reaction and late-stage functionalization of bioactive compounds is possible, providing the opportunity to utilize the cyclopropane ring as a masked β-chloro ketone in a reaction sequence. We propose a light-driven radical chain reaction initiated by the reaction of diluted hydrochloric and nitric acid to produce small quantities of molecular chlorine. The mechanistic hypothesis is supported by
- Published
- 2019
21. Pathogenic H elicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system
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Giovanni Suarez, James A. D. Good, Martín Gómez, Carrie L. Shaffer, Fredrik Almqvist, Keith T. Wilson, Maria Blanca Piazuelo, Pelayo Correa, Eric P. Skaar, Judith Romero-Gallo, Johanna C. Sierra, Richard M. Peek, Alberto G. Delgado, M E Whitaker, Maria Hadjifrangiskou, Matthew G. Varga, and Uma Krishna
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DNA, Bacterial ,0301 basic medicine ,Cancer Research ,Carcinogenesis ,medicine.disease_cause ,Article ,Helicobacter Infections ,Microbiology ,Type IV Secretion Systems ,03 medical and health sciences ,0302 clinical medicine ,Bacterial Proteins ,Stomach Neoplasms ,Genetics ,medicine ,Humans ,CagA ,Molecular Biology ,Mutation ,Innate immune system ,Helicobacter pylori ,biology ,TLR9 ,Cancer ,Biological Transport ,medicine.disease ,biology.organism_classification ,3. Good health ,Toll-Like Receptor 9 ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology - Abstract
Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.
- Published
- 2016
22. Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
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Olli Salin, Patrik Engström, Wael Bahnan, Åsa Gylfe, James A. D. Good, Fredrik Almqvist, Sven Bergström, Carlos Núñez-Otero, K. Syam Krishnan, Richard Svensson, Jim Silver, and Per Artursson
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Serotype ,Pyridones ,medicine.drug_class ,Phenotypic screening ,Antibiotics ,Chlamydia trachomatis ,Microbial Sensitivity Tests ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Microbiology ,Structure-Activity Relationship ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Pathogen ,Infectivity ,Microbial Viability ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Chlamydia Infections ,Small molecule ,Virology ,Anti-Bacterial Agents ,0104 chemical sciences ,Thiazoles ,Toxicity ,Molecular Medicine ,HeLa Cells - Abstract
The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 ≤ 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 μM. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.
- Published
- 2016
23. An improved synthesis of 3-[3-(trifluoromethyl)-3H-1,2-diazirin-3-yl]aniline: A key intermediate in the synthesis of photoaffinity probes
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Torbjörn Wixe and Fredrik Almqvist
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chemistry.chemical_compound ,Aniline ,Trifluoromethyl ,chemistry ,010405 organic chemistry ,Yield (chemistry) ,Organic Chemistry ,Drug Discovery ,Organic chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences - Abstract
An improved synthesis of 3-[3-(trifluoromethyl)-3H-1,2-diazirin-3-yflaniline, achieving an overall yield of 38% over seven steps is reported. Only three chromatographic separations were needed and ...
- Published
- 2017
24. A role for the auxin precursor anthranilic acid in root gravitropism via regulation of PIN-FORMED protein polarity and relocalization in Arabidopsis
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Michal Karady, Adeline Rigal, Marta Zwiewka, Stéphanie Robert, Michael Karampelias, Peter Grones, Mateusz Majda, Barbora Pařízková, Ondřej Novák, Deepak Kumar Barange, Karin Ljung, Siamsa M. Doyle, Aleš Pěnčík, and Fredrik Almqvist
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0106 biological sciences ,chemistry.chemical_classification ,0303 health sciences ,Polarity (international relations) ,biology ,Mutant ,food and beverages ,biology.organism_classification ,Subcellular localization ,01 natural sciences ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,Biosynthesis ,Auxin ,Arabidopsis ,Anthranilic acid ,Arabidopsis thaliana ,heterocyclic compounds ,030304 developmental biology ,010606 plant biology & botany - Abstract
SummaryDistribution of auxin within plant tissues is of great importance for developmental plasticity, including root gravitropic growth. Auxin flow is directed by the subcellular polar distribution and dynamic relocalization of auxin transporters such as the PIN-FORMED (PIN) efflux carriers, which can be influenced by the main natural plant auxin indole-3-acetic acid (IAA). Anthranilic acid (AA) is an important early precursor of IAA and previously published studies with AA analogues suggested that AA may also regulate PIN localization.Using Arabidopsis thaliana as a model species, we studied an AA-deficient mutant displaying agravitropic root growth, treated seedlings with AA and AA analogues and transformed lines to over-produce AA while inhibiting its conversion to downstream IAA precursors.We showed that AA rescues root gravitropic growth in the AA-deficient mutant at concentrations that do not rescue IAA levels. Overproduction of AA affects root gravitropism without affecting IAA levels. Treatments with, or deficiency in, AA result in defects in PIN polarity and gravistimulus-induced PIN relocalization in root cells.Our results reveal a previously unknown role for AA in the regulation of PIN subcellular localization and dynamics involved in root gravitropism, which is independent of its better-known role in IAA biosynthesis.
- Published
- 2018
25. Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
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Andrew G. Cairns, Jörgen Ådén, Ryosuke Arakawa, Charles S. Elmore, Magnus Schou, Fredrik Almqvist, Andrea Varrone, Ana Vazquez-Romero, Mohammad Mahdi Moein, and Akihiro Takano
- Subjects
0301 basic medicine ,Physiology ,Peptidomimetic ,Pyridones ,Cognitive Neuroscience ,010402 general chemistry ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Ester prodrug ,In vivo ,Animals ,Prodrugs ,Carbon Radioisotopes ,Alpha-synuclein ,Chemistry ,Brain ,Esters ,Cell Biology ,General Medicine ,Prodrug ,Macaca mulatta ,In vitro ,0104 chemical sciences ,Thiazoles ,030104 developmental biology ,Blood-Brain Barrier ,Positron-Emission Tomography ,Biophysics ,alpha-Synuclein ,Barrier permeability ,Peptidomimetics - Abstract
Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development o...
- Published
- 2018
26. Inhibition of curli assembly and
- Author
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Neha, Jain, Jörgen, Ådén, Kanna, Nagamatsu, Margery L, Evans, Xinyi, Li, Brennan, McMichael, Magdalena I, Ivanova, Fredrik, Almqvist, Joel N, Buxbaum, and Matthew R, Chapman
- Subjects
Amyloid ,Binding Sites ,Escherichia coli Proteins ,Gene Expression ,Amyloidogenic Proteins ,biochemical phenomena, metabolism, and nutrition ,Biological Sciences ,Kinetics ,Protein Aggregates ,Biofilms ,Escherichia coli ,Humans ,Prealbumin ,Protein Interaction Domains and Motifs ,Protein Multimerization ,Protein Binding - Abstract
Functional amyloids, like curli, contribute to biofilm development by uropathogenic Escherichia coli and other Gram-negative bacteria. Biofilms allow pathogens to subvert immune defenses and antibiotic treatments. Therefore, strategies to interrupt bacterial biofilm formation are urgently required. Here, we discovered that human transthyretin potently inhibits biofilm formation by E. coli and Bacillus subtilis. Transthyretin inhibits biofilm formation by preventing curli proteins from adopting the functional amyloid state that supports biofilm development. To our knowledge, this report of amyloid-dependent biofilm inhibition by a human protein with no significant bactericidal or bacteriostatic activity is unique. The observations indicate that a conformational relationship relevant to a set of specific protein–protein interactions, independent of primary sequence, can be functional across biological kingdoms.
- Published
- 2017
27. Thiazolino 2-Pyridone Amide Isosteres As Inhibitors of Chlamydia trachomatis Infectivity
- Author
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Åsa Gylfe, Esmee de Groot, Fredrik Almqvist, Emma Wede, Martina Kulén, Carlos Núñez-Otero, Jim Silver, K. Syam Krishnan, Wael Bahnan, James A. D. Good, Ingela Nilsson, and Sven Bergström
- Subjects
0301 basic medicine ,Sexually transmitted disease ,Antifungal Agents ,Pyridones ,030106 microbiology ,Chlamydia trachomatis ,Biology ,medicine.disease_cause ,Microbiology ,2-Pyridone ,03 medical and health sciences ,chemistry.chemical_compound ,Amide ,Drug Discovery ,medicine ,Humans ,Infectivity ,Mutagenicity Tests ,Eye infection ,medicine.disease ,Virology ,Amides ,Thiazoles ,Trachoma ,chemistry ,Molecular Medicine ,Mutagenicity Test ,HeLa Cells - Abstract
Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability. We present here the synthesis and evaluation of nonhydrolyzable amide isosteres based on this class, leading to highly potent 1,2,3-triazole based infectivity inhibitors (EC50 ≤ 20 nM).
- Published
- 2017
28. Design of a General-Purpose European Compound Screening Library for EU-OPENSCREEN
- Author
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Fredrik Almqvist, Jens Peter von Kries, A. Varnek, Bernd Rupp, Nikita Remez, Jordi Quintana, Gilles Marcou, C. David Andersson, Jordi Mestres, Didier Rognan, Dragos Horvath, Mikael Elofsson, Marcel Hibert, Ronald Kühne, Michael Lisurek, Per-Anders Enqvist, Anna-Lena Gustavsson, Edgar Specker, Ronald Frank, Chimie de la matière complexe (CMC), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Pharmacology ,Self-organizing map ,Protocol (science) ,business.industry ,Organic Chemistry ,Drug Evaluation, Preclinical ,Biology ,Biochemistry ,Data science ,Chemical space ,Biotechnology ,Task (project management) ,Set (abstract data type) ,Drug Discovery ,Molecular Medicine ,media_common.cataloged_instance ,Relevance (information retrieval) ,European Union ,General Pharmacology, Toxicology and Pharmaceutics ,European union ,business ,[CHIM.CHEM]Chemical Sciences/Cheminformatics ,Selection (genetic algorithm) ,media_common - Abstract
This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target- or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.
- Published
- 2014
29. Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines
- Author
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Marvin Johnson, Andrew G. Cairns, Fredrik Almqvist, Roger Olsson, and Deepak Kumar Barange
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Organic Chemistry ,Substrate (chemistry) ,Alkylation ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Reagent ,Pyridine ,Electrophile ,Organic chemistry ,Stereoselectivity ,Physical and Theoretical Chemistry ,Alkyl - Abstract
Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times.
- Published
- 2016
30. Structural basis for glutathione-mediated activation of the virulence regulatory protein PrfA in Listeria
- Author
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Afshan Begum, Jörgen Johansson, Christin Grundström, A. Elisabeth Sauer-Eriksson, Uwe Sauer, Mikael J. Lindberg, Michael N. Hall, and Fredrik Almqvist
- Subjects
0301 basic medicine ,DNA, Bacterial ,030106 microbiology ,Allosteric regulation ,Amino Acid Motifs ,Glycine ,Biology ,medicine.disease_cause ,Crystallography, X-Ray ,DNA-binding protein ,03 medical and health sciences ,chemistry.chemical_compound ,Listeria monocytogenes ,Bacterial Proteins ,Transcription (biology) ,medicine ,Regulation of gene expression ,Multidisciplinary ,Virulence ,Activator (genetics) ,Gene Expression Regulation, Bacterial ,biochemical phenomena, metabolism, and nutrition ,Biological Sciences ,Glutathione ,Cytosol ,030104 developmental biology ,Biochemistry ,chemistry ,Trans-Activators ,Protein Multimerization ,DNA ,Peptide Termination Factors ,Protein Binding ,Transcription Factors - Abstract
Infection by the human bacterial pathogen Listeria monocytogenes is mainly controlled by the positive regulatory factor A (PrfA), a member of the Crp/Fnr family of transcriptional activators. Published data suggest that PrfA requires the binding of a cofactor for full activity, and it was recently proposed that glutathione (GSH) could fulfill this function. Here we report the crystal structures of PrfA in complex with GSH and in complex with GSH and its cognate DNA, the hly operator PrfA box motif. These structures reveal the structural basis for a GSH-mediated allosteric mode of activation of PrfA in the cytosol of the host cell. The crystal structure of PrfAWT in complex only with DNA confirms that PrfAWT can adopt a DNA binding-compatible structure without binding the GSH activator molecule. By binding to PrfA in the cytosol of the host cell, GSH induces the correct fold of the HTH motifs, thus priming the PrfA protein for DNA interaction.
- Published
- 2016
31. Structure-based design of inhibitors targeting PrfA, the master virulence regulator in Listeria monocytogenes
- Author
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Jörgen Johansson, Christin Grundström, Fredrik Almqvist, Martina Kulén, Elisabeth Sauer-Eriksson, Marie Lindgren, and Uwe Sauer
- Subjects
Regulator ,Virulence ,Biology ,Condensed Matter Physics ,medicine.disease_cause ,Biochemistry ,Microbiology ,Inorganic Chemistry ,Listeria monocytogenes ,Structural Biology ,medicine ,Structure based ,General Materials Science ,Physical and Theoretical Chemistry - Published
- 2018
32. Four-Component Assembly of Natural-Product-Like Ring-Fused Isoquinuclidines
- Author
-
Magnus Sellstedt, Hung The Dang, G. Krishna Prasad, Uwe Sauer, and Fredrik Almqvist
- Subjects
chemistry.chemical_compound ,Natural product ,Four component ,chemistry ,Organic Chemistry ,Organic chemistry ,Physical and Theoretical Chemistry ,Ring (chemistry) - Abstract
A four-component reaction between formyl-substituted 2-pyridones, aldehydes, amines, and activated alkenes has been developed. The resulting products are ring-fused natural-product-like isoquinucli ...
- Published
- 2013
33. Asymmetric Synthesis of 2,4,5-Trisubstituted Δ2-Thiazolines
- Author
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Fredrik Almqvist, Hanna Nelander, and Christoffer Bengtsson
- Subjects
heterocycles ,Biological Products ,Full Paper ,thiazolines ,Chemistry ,asymmetric synthesis ,Organic Chemistry ,Enantioselective synthesis ,Stereoisomerism ,General Chemistry ,Catalysis ,acyl migration ,Thiazoles ,Organic chemistry ,unnatural amino acids - Abstract
Δ(2)-Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to 2,4,5-trisubstituted Δ(2)-thiazolines. These Δ(2)-thiazolines were synthesized from readily accessible/commercially available α,β-unsaturated methyl esters through a Sharpless asymmetric dihydroxylation and an O→N acyl migration reaction as key steps. The final products were obtained in good yields with up to 97 % enantiomeric excess.
- Published
- 2013
34. Age-specific prevalence of intellectual disability in Finland at the beginning of new millennium - multiple register method
- Author
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Markus Kaski, Matti Iivanainen, Lauri J. Virta, Hannu Westerinen, and Fredrik Almqvist
- Subjects
National health ,Younger age ,business.industry ,Rehabilitation ,medicine.disease ,Age specific ,Psychiatry and Mental health ,Neurology ,Arts and Humanities (miscellaneous) ,Register (music) ,Age groups ,Intellectual disability ,medicine ,National study ,Pooled data ,Neurology (clinical) ,10. No inequality ,business ,Demography - Abstract
Background In the national study of multiple registers in 2000, the average prevalence of intellectual disability (ID) was 0.70%, with marked differences by age group (range 0.38–0.96%) – what are these differences in detail, and can they be understood? Method This study was based on two national health registers and six social benefit registers. Prevalence of ID was calculated by 1-year age cohorts. Results The multiple register prevalence of ID increased steadily from 0.20% in the first life year to 0.74% (male: 0.90%, female: 0.58%) at 10 years. For boys, the rate fell to 0.71% at 11 years. For both sexes, a steady increase was noted in the distribution up to 40 years (male: 0.84%, female: 0.73%), followed by a sharper increase to the maximum prevalence (male: 1.19% at 48 years, female: 1.05% at 50 years). At the pension age of 66 years, a sudden drop to 0.49% occurred for men and women. Different registers gave very different age distributions. Conclusions By examining the data by 1-year age cohorts, and by understanding the role of each register, it could be deduced that a proportion of cases in younger age groups is lacking, and a remarkable proportion of elderly ID persons is missing from the pooled data. The findings were more difficult to interpret, if the data were grouped into bigger age groups.
- Published
- 2013
35. ChemInform Abstract: Synthesis of Multiring Fused 2-Pyridones via a Nitrene Insertion Reaction: Fluorescent Modulators of α-Synuclein Amyloid Formation
- Author
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K. Syam Krishnan, Pardeep Singh, Fredrik Almqvist, Erik Chorell, Joergen Aaden, Tomas Kindahl, and Pernilla Wittung-Stafshede
- Subjects
chemistry.chemical_compound ,Amyloid ,Stereochemistry ,Chemistry ,Insertion reaction ,Nitrene ,α synuclein ,General Medicine ,Fluorescence - Published
- 2016
36. Clinical and MRI outcome of an osteochondral scaffold plug for the treatment of cartilage lesions in the knee
- Author
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Aad, Dhollander, Peter, Verdonk, Karl Fredrik, Almqvist, Rene, Verdonk, and Jan, Victor
- Subjects
Adult ,Cartilage, Articular ,Male ,Adolescent ,Knee Joint ,Tissue Scaffolds ,Middle Aged ,Magnetic Resonance Imaging ,Young Adult ,Chondrocytes ,Humans ,Female ,Orthopedic Procedures ,Prospective Studies ,Cartilage Diseases ,Follow-Up Studies - Abstract
Conflicting clinical outcomes have been reported recently with the use of an osteochondral scaffold plugs for cartilage repair in the knee. In this study, twenty patients were consecutively treated for their cartilage lesions with the synthetic plug technique. These patients were prospectively clinically evaluated with a mean follow-up of 34.15 months. Magnetic resonance imaging (MRI) was used for morphologic analysis of the cartilage repair. The patients included in this study showed a significant gradual clinical improvement after the osteochondral scaffold plug. However, this clinical improvement was not confirmed by the MRI findings of this cohort study. Subchondral bone changes were seen in all patients on MRI and deficient filling of the defect was noticed in in 30.7% of the cases at 24 months of follow-up. There was no evidence found to support osteoconductive bone ingrowth. Therefore, the use of this type of osteochondral scaffold plug in osteochondral repair is questionable. Level of evidence: IV.
- Published
- 2016
37. Traumatic Lesions in a Stable Knee: Masterly Neglect - Meniscectomy - Repair
- Author
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Jürgen Hoeher, René Verdonk, Pieter Vansintjan, Maurice Balke, K. Fredrik Almqvist, and Peter Verdonk
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,media_common.quotation_subject ,Physical examination ,Meniscus (anatomy) ,Knee Joint ,Partial resection ,Asymptomatic ,eye diseases ,Neglect ,Surgery ,medicine.anatomical_structure ,Refixation ,Medicine ,Tears ,sense organs ,medicine.symptom ,business ,media_common - Abstract
Traumatic meniscal tears are common injuries of the knee joint. In order to choose the treatment modality that best suits the needs of the individual patient, a well-structured assessment and thorough clinical examination are mandatory. An MRI is helpful for planning the procedure and defining the exact tear location. Small asymptomatic tears can often be treated conservatively (“masterly neglect”). If surgical treatment is necessary, as much viable meniscus tissue as possible should be preserved. Tears of the vascular zone usually can be treated by refixation, whereas tears of the avascular zone are treated by partial resection.
- Published
- 2016
38. Childhood predictors of becoming a teenage mother among Finnish girls
- Author
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Lauri Sillanmäki, Fredrik Almqvist, Tuula Tamminen, Hans Helenius, Maria Heinze, Jorma Piha, Solja Niemelä, Andre Sourander, Kirsti Kumpulainen, and Venla Lehti
- Subjects
Teenage pregnancy ,education.field_of_study ,medicine.medical_specialty ,business.industry ,05 social sciences ,Population ,Obstetrics and Gynecology ,General Medicine ,medicine.disease ,Mental health ,03 medical and health sciences ,0302 clinical medicine ,Conduct disorder ,medicine ,0501 psychology and cognitive sciences ,030212 general & internal medicine ,Young adult ,Risk factor ,education ,Psychiatry ,business ,Psychosocial ,050104 developmental & child psychology ,Demography ,Cohort study - Abstract
Objective. To study predictive associations between psychosocial factors at age 8 and becoming a mother under the age of 20. Design: Prospective follow-up study. Setting: Finland. Population. 2867 girls born in 1981. Methods. Information on family background and psychiatric symptoms was collected at age 8. The associations between these factors and becoming a teenage mother were analyzed using logistic regression analysis. Main outcome measures. Data on births by the age of 20 collected from the hospital discharge register. Results. 128 girls (4.8%) had given birth at the age of 15–19 years. Childhood conduct problems and hyperactive problems, having young mother and family structure other than two biological parents had an independent association with becoming a teenage mother. Conclusions. Girls with externalizing type of problems in childhood have an increased risk of becoming teenage mothers. These problems may also complicate their motherhood.
- Published
- 2012
39. The C-Terminal Repeating Units of CsgB Direct Bacterial Functional Amyloid Nucleation
- Author
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Neal D. Hammer, Yizhou Zhou, Matthew P. Badtke, Fredrik Almqvist, Kristoffer Brännström, Bryan A. McGuffie, Matthew George Chapman, Jason E. Gestwicki, Ashley A. Reinke, and Anders Olofsson
- Subjects
Amyloid ,Protein subunit ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,Protein Structure, Secondary ,Article ,Cell membrane ,Protein structure ,Bacterial Proteins ,Structural Biology ,mental disorders ,Escherichia coli ,medicine ,Amino Acid Sequence ,Molecular Biology ,Peptide sequence ,Sequence Deletion ,Mutation ,Escherichia coli Proteins ,Cell Membrane ,Terminal Repeat Sequences ,In vitro ,Protein Subunits ,medicine.anatomical_structure ,Biochemistry ,Protein Multimerization ,Peptides - Abstract
Curli are functional amyloids produced by enteric bacteria. The major curli fiber subunit, CsgA, self-assembles into an amyloid fiber in vitro. The minor curli subunit protein, CsgB, is required for CsgA polymerization on the cell surface. Both CsgA and CsgB are composed of five predicted β-strand-loop-β-strand-loop repeating units that feature conserved glutamine and asparagine residues. Because of this structural homology, we proposed that CsgB might form an amyloid template that initiates CsgA polymerization on the cell surface. To test this model, we purified wild-type CsgB and found that it self-assembled into amyloid fibers in vitro. Preformed CsgB fibers seeded CsgA polymerization as did soluble CsgB added to the surface of cells secreting soluble CsgA. To define the molecular basis of CsgB nucleation, we generated a series of mutants that removed each of the five repeating units. Each of these CsgB deletion mutants was capable of self-assembly in vitro. In vivo, membrane-localized mutants lacking the first, second, or third repeating units were able to convert CsgA into fibers. However, mutants missing either the fourth or fifth repeating units were unable to complement a csgB mutant. These mutant proteins were not localized to the outer membrane but were instead secreted into the extracellular milieu. Synthetic CsgB peptides corresponding to repeating units 1, 2, and 4 self-assembled into ordered amyloid polymers, while peptides corresponding to repeating units 3 and 5 did not, suggesting that there are redundant amyloidogenic domains in CsgB. Our results suggest a model where the rapid conversion of CsgB from unstructured protein to a β-sheet-rich amyloid template anchored to the cell surface is mediated by the C-terminal repeating units.
- Published
- 2012
40. Childhood bullying and becoming a young father in a national cohort of Finnish boys
- Author
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Kirsti Kumpulainen, Tuula Tamminen, Jorma Piha, Anat Brunstein Klomek, Irma Moilanen, Venla Lehti, Fredrik Almqvist, and Andre Sourander
- Subjects
4. Education ,education ,05 social sciences ,Poison control ,Human factors and ergonomics ,Peer group ,social sciences ,General Medicine ,16. Peace & justice ,Suicide prevention ,Occupational safety and health ,Developmental psychology ,03 medical and health sciences ,0302 clinical medicine ,Arts and Humanities (miscellaneous) ,030225 pediatrics ,Injury prevention ,Developmental and Educational Psychology ,0501 psychology and cognitive sciences ,Young adult ,Psychology ,Psychosocial ,General Psychology ,050104 developmental & child psychology - Abstract
Childhood bullying is known to be associated with various adverse psychosocial outcomes in later life. No studies exist on its association with becoming a young father. The study is based on a national cohort, which included 2,946 Finnish boys at baseline in 1989. Information on bullying was collected from children, their parents and their teachers. Follow-up data on becoming a father under the age of 22 were collected from a nationwide register. The follow-up sample included 2,721 boys. Bullying other children frequently was significantly associated with becoming a young father independently of being victimized, childhood psychiatric symptoms and parental educational level. Being a victim of bullying was not associated with becoming a young father when adjusted for possible confounders. When the co-occurrence of bullying and victimization was studied, it was found that being a bully-victim, but not a pure bully or a pure victim, is significantly associated with becoming a young father. This study adds to other studies, which have shown that the risk profile and relational patterns of bully-victims differ from those of other children, and it emphasizes the importance of including peer relationships when studying young fathers.
- Published
- 2012
41. Design, synthesis and evaluation of triazole functionalized ring-fused 2-pyridones as antibacterial agents
- Author
-
Anders E. G. Lindgren, Christoffer Bengtsson, Fredrik Almqvist, and Hanna Uvell
- Subjects
Pyridones ,Triazole ,Chemistry Techniques, Synthetic ,Ring (chemistry) ,2-Pyridone ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Organic chemistry ,Structure–activity relationship ,Mode of action ,Pharmacology ,Organic Chemistry ,General Medicine ,Triazoles ,Combinatorial chemistry ,humanities ,Anti-Bacterial Agents ,Antibacterial ,chemistry ,Design synthesis ,Antibacterial resistance ,Biofilms ,Drug Design ,Pilicide ,Huisgen 1,3-dipolar cycloaddition - Abstract
Antibacterial resistance is today a worldwide problem and the demand for new classes of antibacterial agents with new mode of action is enormous. In the strive for new antibacterial agents that inhibit pilus assembly, an important virulence factor, routes to introduce triazoles in position 8 and 2 of ring-fused bicyclic 2-pyridones have been developed. This was made via Sonogashira couplings followed by Huisgen 1,3-dipolar cycloadditions. The method development made it possible to introduce a diverse series of substituted triazoles and their antibacterial properties were tested in a whole cell pili-dependent biofilm assay. Most of the twenty four candidates tested showed low to no activity but interestingly three compounds, one 8-substituted and two 2-substituted, showed promising activities with EC50's between 9 and 50 μM.
- Published
- 2012
42. Childhood predictors of antipsychotic use among young people in Finland
- Author
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Hans Helenius, Andre Sourander, Kirsti Kumpulainen, Jukka Huttunen, Jorma Piha, Lauri Sillanmäki, Fredrik Almqvist, Tuula Tamminen, David Gyllenberg, and Irma Moilanen
- Subjects
medicine.medical_specialty ,education.field_of_study ,Epidemiology ,business.industry ,medicine.medical_treatment ,Population ,Poison control ,medicine.disease ,Schizophrenia ,Injury prevention ,medicine ,Pharmacology (medical) ,Young adult ,Psychiatry ,Antipsychotic ,education ,business ,Psychopathology - Abstract
OBJECTIVE: Information on who uses antipsychotic medication is limited to cross-sectional data. The objective of this study was to study the patterns of psychopathology at age 8 years and antipsychotic use between the ages of 12 and 25 years. METHODS: A total of 5525 subjects from the Finnish Nationwide 1981 birth cohort were linked to the National Prescription Register and the Hospital Discharge Register between 1994 and 2005. Information about parent-reported and teacher-reported conduct, hyperkinetic and emotional symptoms, and self-reported depressive symptoms was gathered at age 8 years. Information about antipsychotic use and about psychiatric disorders treated in hospitals between the ages of 12 and 25 years was register based. Diagnostic classes of hospital treatment included non-affective psychoses, affective disorders, and other psychiatric disorders. RESULTS: The cumulative incidence of antipsychotic use by age 25 years was 2.8% among men (n = 69) and 2.1% among women (n = 55). In both sexes, living with other than two biological parents at age 8 years was associated with antipsychotic use, and three fourths of antipsychotic users had been treated for psychiatric disorders in a hospital. Among men, the most common hospital diagnosis was non-affective psychoses (44% of all antipsychotic users), and antipsychotic use was associated with childhood conduct problems. Among women, the most common hospital diagnosis was affective disorders (38% of all antipsychotic users), and antipsychotic use was associated with emotional problems and self-reported depressive symptoms in childhood. CONCLUSIONS: Antipsychotic use in adolescence and young adulthood is different among men versus women both with regard to hospital diagnoses and childhood psychiatric problems. Copyright © 2012 John Wiley & Sons, Ltd. Language: en
- Published
- 2012
43. Pain at age eight as a predictor of antidepressant medication use by age 24: Findings from the Finnish nationwide 1981 birth cohort study
- Author
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Andre Sourander, Tuula Tamminen, Fredrik Almqvist, Minna Aromaa, Lauri Sillanmäki, David Gyllenberg, Kirsti Kumpulainen, Irma Moilanen, Terhi Luntamo, and Jorma Piha
- Subjects
Male ,medicine.medical_specialty ,Abdominal pain ,Pediatrics ,Adolescent ,Population ,Pain ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Prevalence ,Humans ,Medicine ,Medical prescription ,Child ,Psychiatry ,education ,Prospective cohort study ,Finland ,Depression (differential diagnoses) ,education.field_of_study ,Dose-Response Relationship, Drug ,Depression ,business.industry ,Hazard ratio ,Confounding ,Headache ,Antidepressive Agents ,Abdominal Pain ,3. Good health ,Psychiatry and Mental health ,Clinical Psychology ,Female ,medicine.symptom ,business ,Psychosocial ,030217 neurology & neurosurgery - Abstract
Background The existing knowledge about long-term psychosocial consequences of childhood pain is scarce. The current study investigated childhood pain symptoms as potential risk factors for antidepressant use in adolescence and early adulthood. Methods A representative sample of eight-year-old children (n = 6017) and their parents were asked about the prevalence of the child's headache, abdominal pain, and unspecified pain symptoms. The associations with antidepressant purchases by age 24, based on the nationwide prescription register, were analyzed separately for each symptom and each reporter. Sex, parental educational level, and child-, parent- and teacher-reported child's psychiatric symptoms at baseline were included as confounding variables. Results In the sex-adjusted model, the child's own report of headache and other pains, and the parents' report of their child's abdominal pain, predicted antidepressant purchases. When confounding variables were included in the final model, only the child's own report of headache predicted antidepressant use with a dose–response relationship. The hazard ratios and 95% confidence intervals for frequent and for almost daily headache were 1.6 (1.3–2.0) and 2.1 (1.5–2.9), respectively, in the sex-adjusted model, and 1.5 (1.2–1.8) and 1.7 (1.2–2.5) in the final model. Limitations The assessment of each pain symptom was based on one question for each reporter. The specific indications for the described medication could not be defined. Conclusions Health care professionals should also ask children themselves about the pain symptoms. They should be aware that children with pain are at increased risk of suffering later from conditions that require antidepressant treatment.
- Published
- 2012
44. Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms
- Author
-
Sofie Edvinsson, Erik Chorell, Jerome S. Pinkner, Fredrik Almqvist, Scott J. Hultgren, Christoffer Bengtsson, Erik Rosenbaum, Corinne K. Cusumano, and Lennart B.-Å. Johansson
- Subjects
Boron Compounds ,Models, Molecular ,Peptidomimetic ,Stereochemistry ,Virulence ,biological activity ,Crystallography, X-Ray ,medicine.disease_cause ,coumarin ,Catalysis ,Pilus ,Structure-Activity Relationship ,chemistry.chemical_compound ,Coumarins ,Escherichia coli ,medicine ,Curli assembly ,antivirulence ,Structure–activity relationship ,Fluorescent Dyes ,Chemistry ,Escherichia coli Proteins ,Organic Chemistry ,Biofilm ,General Chemistry ,Full Papers ,Anti-Bacterial Agents ,Biochemistry ,structure–activity relationships ,fluorescence ,BODIPY - Abstract
Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.
- Published
- 2012
45. Synthesis of Multiring Fused 2-Pyridones via a Nitrene Insertion Reaction: Fluorescent Modulators of α-Synuclein Amyloid Formation
- Author
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Pardeep Singh, Fredrik Almqvist, Jörgen Ådén, Tomas Kindahl, Erik Chorell, K. Syam Krishnan, and Pernilla Wittung-Stafshede
- Subjects
Molecular Structure ,Peptidomimetic ,Stereochemistry ,Chemistry ,Pyridones ,Nitrene ,Organic Chemistry ,Biochemistry ,Fluorescence ,Heterocyclic Compounds, 4 or More Rings ,Catalysis ,chemistry.chemical_compound ,Thiazoles ,Insertion reaction ,Intramolecular force ,alpha-Synuclein ,Molecule ,Imines ,Physical and Theoretical Chemistry ,Amyloid (mycology) ,Amination - Abstract
© 2015 American Chemical Society. An efficient, straightforward method for the synthesis of thiazolo-2-pyridone embedded peptidomimetic polyheterocycles via a catalyst-free, microwave-assisted, intramolecular C-H amination reaction is reported. All the synthesized polyheterocycles were evaluated for their fluorescent properties and effect on α-synuclein amyloid formation.
- Published
- 2015
46. Patients with univentricular heart in early childhood: parenting stress and child behaviour
- Author
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Anne Sarajuuri, Eero Jokinen, F Schmitt, Tuula Lönnqvist, and Fredrik Almqvist
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Case-control study ,Parenting stress ,General Medicine ,030204 cardiovascular system & hematology ,Standard score ,medicine.disease ,Hypoplastic left heart syndrome ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,medicine ,Early childhood ,Prospective cohort study ,Child Behavior Checklist ,business ,Child behaviour - Abstract
Aims: To assess perceptions of child behaviour and parenting stress among the parents of young children with hypoplastic left heart syndrome (HLHS) and other forms of functionally univentricular heart defects (UVH). Methods: As part of our prospective nation-wide neurodevelopmental follow-up study, the parents of 23 patients with HLHS, 14 with UVH and 46 healthy controls at the mean age of 18 months received the questionnaires Child Behavior Checklist and Parenting Stress Index. Results: The reported level of total parenting stress was significantly higher among the mothers (mean score 241 vs 205, p
- Published
- 2011
47. What is the long-term outcome of boys who steal at age eight? Findings from the Finnish nationwide 'From A Boy To A Man' birth cohort study
- Author
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Sturla Fossum, Fredrik Almqvist, Henrik Elonheimo, Irma Moilanen, Kirsti Kumpulainen, Tuula Tamminen, Jorma Piha, Terja Ristkari, John A. Rønning, and Andre Sourander
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Health (social science) ,Social Psychology ,Epidemiology ,Population ,Theft ,Poison control ,Suicide, Attempted ,Child Behavior Disorders ,Suicide prevention ,Cohort Studies ,Risk Factors ,Surveys and Questionnaires ,Injury prevention ,Prevalence ,medicine ,Humans ,Child ,Psychiatry ,education ,Finland ,health care economics and organizations ,education.field_of_study ,Psychopathology ,Suicide attempt ,business.industry ,Aggression ,Age Factors ,Human factors and ergonomics ,Antisocial Personality Disorder ,Criminals ,body regions ,Psychiatry and Mental health ,Cross-Sectional Studies ,Logistic Models ,medicine.symptom ,business - Abstract
OBJECTIVE: The aim was to study predictive associations between childhood stealing behavior at the of age 8 years with later psychiatric disorders, criminality or suicide attempts and completed suicides up to the age 25 years in a large representative population-based birth cohort. METHOD: The sample includes 2,592 Finnish males born in 1981 with information about stealing from both parents and teachers. Information about psychiatric disorders, criminality, suicide attempts requiring hospital admission and completed suicides was gathered from four different Finnish nationwide registries until the study participants were 25 years old. RESULTS: One out of ten boys had stealing behavior during the previous 12 months. After adjusting for parental education level and conduct problems or hyperactivity (i.e. potential confounds), stealing at eight independently predicted substance use and antisocial personality disorders, and high level of crimes. Stealing was also associated with completed suicide or severe suicide attempt requiring hospital admission. Comorbid stealing and frequent aggression had the strongest predictive association with any psychiatric diagnosis, crime and completed suicide or severe suicide attempt, while stealing without aggression was not associated with any of the negative outcomes. CONCLUSIONS: Stealing accompanied with aggressivity at age eight is predictive of wide range of adversities. However, no increased risk was observed among the group with stealing behaviors but without aggression. Language: en
- Published
- 2011
48. Depressed youth: treatment outcome and changes in family functioning in individual and family therapy
- Author
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Fredrik Almqvist, Kati Heinonen, Anu-Katriina Pesonen, and Finn Ferdinand Garoff
- Subjects
Family therapy ,050103 clinical psychology ,Psychodynamic psychotherapy ,medicine.medical_specialty ,Social Psychology ,Family functioning ,05 social sciences ,Treatment outcome ,Clinical Psychology ,050902 family studies ,medicine ,0501 psychology and cognitive sciences ,In patient ,0509 other social sciences ,Psychiatry ,Psychology ,Social Sciences (miscellaneous) ,After treatment ,Depressive symptoms ,Depression (differential diagnoses) ,Clinical psychology - Abstract
This study explores the role of family functioning in therapeutic change in focused individual psychodynamic psychotherapy (FIPP) and time-limited systems integrative family therapy (SIFT) for depressed children and adolescents. After a screening process, 72 participants aged 8 to 15 were randomized to either FIPP or time-limited SIFT. Assessments took place prior to, at the end of, and 6 months after treatment. Families in both SIFT and FIPP showed a small but significant and sustained improvement in family functioning by the end of treatment in both mothers' self-reports and family therapists' assessments. Better family functioning at baseline in mothers' self-reports and improved family functioning during SIFT, as assessed by family therapists, predicted a sustained decrease in self-reported depressive symptoms. Results indicated that time-limited SIFT may be more effective with younger children and in patients without a diagnosis of double depression than adolescents.
- Published
- 2011
49. Childhood bullying behaviors at age eight and substance use at age 18 among males. A nationwide prospective study
- Author
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Lauri Sillanmäki, Hans Helenius, Tuula Tamminen, Kirsti Kumpulainen, Anat Brunstein-Klomek, Irma Moilanen, Fredrik Almqvist, Andre Sourander, Jorma Piha, and Solja Niemelä
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Substance-Related Disorders ,Child psychopathology ,Medicine (miscellaneous) ,Poison control ,Toxicology ,Suicide prevention ,Occupational safety and health ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Injury prevention ,Humans ,Medicine ,0501 psychology and cognitive sciences ,Prospective Studies ,030212 general & internal medicine ,Child ,Psychiatry ,Finland ,business.industry ,4. Education ,05 social sciences ,Age Factors ,Bullying ,Human factors and ergonomics ,16. Peace & justice ,Psychiatry and Mental health ,Clinical Psychology ,Population study ,business ,050104 developmental & child psychology ,Psychopathology - Abstract
Childhood bullying behaviors (bullying and victimization) were studied as risk factors for substance use among Finnish males. The study design was a nationwide prospective general population study, where information was collected in 1989 and 1999. Bullying behaviors and childhood psychopathology at age eight were collected from teachers, parents and boys themselves. At age 18, self-reports of frequent drunkenness (once a week or more often), daily heavy smoking (10 cigarettes or more per day), and illicit drug use during the past six months were obtained from 78% of the boys attending the study at age eight (n=2946). Being frequently victimized at age eight predicted daily heavy smoking, and this was evident even after adjusting for childhood family background, psychopathology at age eight and at age 18, and other forms of substance use. In multivariate analysis, bullying others frequently predicted illicit drug use, while being a victim of bullying associated with a lower occurrence of illicit drug use. Bullying behaviors had no association with frequent drunkenness independent of other factors. Accordingly, being a victim of bullying predisposes in particular to subsequent smoking. Bullying others in childhood can be regarded as an early indicator to illicit drug use later in life. The screening and intervention possibilities in order to recognize the risk group for later health compromising behaviors are emphasized. Language: en
- Published
- 2011
50. Reactions between Grignard reagents and heterocyclic N-oxides: Stereoselective synthesis of substituted pyridines, piperidines, and piperazines
- Author
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Fredrik Almqvist, Roger Olsson, and Hans Andersson
- Subjects
chemistry.chemical_classification ,Pyrazine ,Aryl ,Organic Chemistry ,Chiral ligand ,Sparteine ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Reagent ,Pyridine ,medicine ,Organic chemistry ,Stereoselectivity ,Physical and Theoretical Chemistry ,Alkyl ,medicine.drug - Abstract
In this perspective we discuss the recent developments of stereoselective synthesis of substituted pyridines, piperidines, and piperazines from cheap and commercially readily available starting materials. Pyridine N-oxides and pyrazine N-oxides are reacted with alkyl, aryl, alkynyl and vinyl Grignard reagents to give a diverse set of heterocycles in high yields. Optically active substituted piperazines are obtained by an asymmetric reaction from pyrazine N-oxides using sparteine as chiral ligand. In addition, a stereoselective synthesis of dienal-oximes from the reaction between pyridine N-oxides and Grignard reagents is presented, which results in a useful intermediate for the synthesis of a diverse set of compounds.
- Published
- 2011
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