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| 2. |
- Santonocito, M., et al.
(författare)
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Molecular characterization of exosomes and their microRNA cargo in human follicular fluid: bioinformatic analysis reveals that exosomal microRNAs control pathways involved in follicular maturation
- 2014
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282. ; 102:6, s. 1751-U590
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To characterize well-represented microRNAs in human follicular fluid (FF) and to ascertain whether they are cargo of FF exosomes and whether they are involved in the regulation of follicle maturation. Design: FF exosomes were characterized by nanosight, flow cytometry, and exosome-specific surface markers. Expression microRNA profiles from total and exosomal FF were compared with those from plasma of the same women. Patient(s): Fifteen healthy women who had undergone intracytoplasmic sperm injection. Main Outcome Measure(s): TaqMan low-density array to investigate the expression profile of 384 microRNAs; DataAssist and geNorm for endogenous control identification; significance analysis of microarrays to identify differentially expressed microRNAs; nanosight, flow-cytometry, and bioanalyzer for exosome characterization; bioinformatic tools for microRNAs target prediction, gene ontology, and pathway analysis. Result(s): We identified 37 microRNAs upregulated in FF as compared with plasma from the same women. Thirty-two were carried by microvesicles that showed the well-characterized exosomal markers CD63 and CD81. These FF microRNAs are involved in critically important pathways for follicle growth and oocyte maturation. Specifically, nine of them target and negatively regulate mRNAs expressed in the follicular microenvironment encoding inhibitors of follicle maturation and meiosis resumption. Conclusion(s): This study identified a series of exosomal microRNAs that are highly represented in human FF and are involved in follicular maturation. They could represent noninvasive biomarkers of oocyte quality in assisted reproductive technology. (C) 2014 by American Society for Reproductive Medicine.
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| 3. |
- Carrillo, M., et al.
(författare)
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High-resolution crystal structures of transient intermediates in the phytochrome photocycle
- 2021
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Ingår i: Structure. - : Elsevier BV. - 0969-2126. ; 29:7, s. 743-
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Tidskriftsartikel (refereegranskat)abstract
- Phytochromes are red/far-red light photoreceptors in bacteria to plants, which elicit a variety of important physiological responses. They display a reversible photocycle between the resting Pr state and the light-activated Pfr state. Light signals are transduced as structural change through the entire protein to modulate its activity. It is unknown how the Pr-to-Pfr interconversion occurs, as the structure of intermediates remains notoriously elusive. Here, we present short-lived crystal structures of the photosensory core modules of the bacteriophytochrome from myxobacterium Stigmatella aurantiaca captured by an X-ray free electron laser 5 ns and 33 ms after light illumination of the Pr state. We observe large structural displacements of the covalently bound bilin chromophore, which trigger a bifurcated signaling pathway that extends through the entire protein. The snapshots show with atomic precision how the signal progresses from the chromophore, explaining how plants, bacteria, and fungi sense red light.
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| 4. |
- Claesson, Elin, 1989, et al.
(författare)
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The primary structural photoresponse of phytochrome proteins captured by a femtosecond X-ray laser
- 2020
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Ingår i: eLife. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation. The data reveal a twist of the D-ring, which leads to partial detachment of the chromophore from the protein. Unexpectedly, the conserved so-called pyrrole water is photodissociated from the chromophore, concomitant with movement of the A-ring and a key signaling aspartate. The changes are wired together by ultrafast backbone and water movements around the chromophore, channeling them into signal transduction towards the output domains. We suggest that the observed collective changes are important for the phytochrome photoresponse, explaining the earliest steps of how plants, fungi and bacteria sense red light.
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| 5. |
- Lolli, M. L., et al.
(författare)
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Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3
- 2019
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Ingår i: Acs Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 10:4, s. 437-443
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Tidskriftsartikel (refereegranskat)abstract
- Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Both compounds were found to target AKR1C3 in a selective manner. In particular, hydroxyfurazan derivative is highly selective for AKR1C3 over the 1C2 isoform (up to 90-times more) and inactive on COX enzymes. High-resolution crystal structure of its complex with AKR1C3 shed light onto the binding mode of the new inhibitors. In cell-based assays (on colorectal and prostate cancer cells), the two indomethacin analogues showed higher potency than indomethacin. Therefore, these two AKR1C3 inhibitors can be used to provide further insight into the role of AKR1C3 in cancer. © 2019 American Chemical Society.
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| 6. |
- Ringleb, PA, et al.
(författare)
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Guidelines for management of ischaemic stroke and transient ischaemic attack 2008
- 2008
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Ingår i: Cerebrovascular diseases (Basel, Switzerland). - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 25:5, s. 457-507
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Tidskriftsartikel (refereegranskat)abstract
- This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.
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| 7. |
- Sanchez, J. C., et al.
(författare)
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High-resolution crystal structures of amyxobacterial phytochrome at cryo and roomtemperatures
- 2019
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Ingår i: Structural Dynamics-Us. - : AIP Publishing. - 2329-7778. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- Phytochromes (PHYs) are photoreceptor proteins first discovered in plants, where they control a variety of photomorphogenesis events. PHYs as photochromic proteins can reversibly switch between two distinct states: a red light (Pr) and a far-red light (Pfr) absorbing form. The discovery of Bacteriophytochromes (BphPs) in nonphotosynthetic bacteria has opened new frontiers in our understanding of the mechanisms by which these natural photoswitches can control single cell development, although the role of BphPs in vivo remains largely unknown. BphPs are dimeric proteins that consist of a photosensory core module (PCM) and an enzymatic domain, often a histidine kinase. The PCM is composed of three domains (PAS, GAF, and PHY). It holds a covalently bound open-chain tetrapyrrole (biliverdin, BV) chromophore. Upon absorption of light, the double bond between BV rings C and D isomerizes and reversibly switches the protein between Pr and Pfr states. We report crystal structures of the wild-type and mutant (His275Thr) forms of the canonical BphP from the nonphotosynthetic myxobacterium Stigmatella aurantiaca (SaBphP2) in the Pr state. Structures were determined at 1.65A degrees and 2.2A degrees (respectively), the highest resolution of any PCM construct to date. We also report the room temperature wild-type structure of the same protein determined at 2.1A degrees at the SPring-8 Angstrom Compact free electron LAser (SACLA), Japan. Our results not only highlight and confirm important amino acids near the chromophore that play a role in Pr-Pfr photoconversion but also describe the signal transduction into the PHY domain which moves across tens of angstroms after the light stimulus. (C) 2019 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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| 8. |
- Bozzola, Tiago, et al.
(författare)
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Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
- 2022
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Ingår i: Acs Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
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| 9. |
- Johansson, Linda C, 1983, et al.
(författare)
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Structure of a photosynthetic reaction centre determined by serial femtosecond crystallography.
- 2013
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Serial femtosecond crystallography is an X-ray free-electron-laser-based method with considerable potential to have an impact on challenging problems in structural biology. Here we present X-ray diffraction data recorded from microcrystals of the Blastochloris viridis photosynthetic reaction centre to 2.8 Å resolution and determine its serial femtosecond crystallography structure to 3.5 Å resolution. Although every microcrystal is exposed to a dose of 33 MGy, no signs of X-ray-induced radiation damage are visible in this integral membrane protein structure.
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| 10. |
- Wahlgren, N., et al.
(författare)
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Mechanical thrombectomy in acute ischemic stroke: Consensus statement by ESO-Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN
- 2016
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 11:1, s. 134-147
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Tidskriftsartikel (refereegranskat)abstract
- The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16-18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN).
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