| 1. |
- Coutard, B., et al.
(författare)
-
The VIZIER project : Preparedness against pathogenic RNA viruses
- 2008
-
Ingår i: Antiviral Research. - : Elsevier BV. - 0166-3542 .- 1872-9096. ; 78:1, s. 37-46
-
Tidskriftsartikel (refereegranskat)abstract
- Life-threatening RNA viruses emerge regularly, and often in an unpredictable manner. Yet, the very few drugs available against known RNA viruses have sometimes required decades of research for development. Can we generate preparedness for outbreaks of the, as yet, unknown viruses? The VIZIER (VIral enZymes InvolvEd in Replication) (http://www.vizier-europe.org/) project has been set-up to develop the scientific foundations for countering this challenge to society. VIZIER studies the most conserved viral enzymes (that of the replication machinery, or replicases) that constitute attractive targets for drug-design. The aim of VIZIER is to determine as many replicase crystal structures as possible from a carefully selected list of viruses in order to comprehensively cover the diversity of the RNA virus universe, and generate critical knowledge that could be efficiently utilized to jump-start research on any emerging RNA virus. VIZIER is a multidisciplinary project involving (i) bioinformatics to define functional domains, (ii) viral genomics to increase the number of characterized viral genomes and prepare defined targets, (iii) proteomics to express, purify, and characterize targets, (iv) structural biology to solve their crystal structures, and (v) pre-lead discovery to propose active scaffolds of antiviral molecules.
|
|
| 2. |
- Andersson, H.O., et al.
(författare)
-
Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
-
Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
-
Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
|
|
| 3. |
- Fogg, M. J., et al.
(författare)
-
Application of the use of high-throughput technologies to the determination of protein structures of bacterial and viral pathogens
- 2006
-
Ingår i: Acta Crystallographica Section D. - 0907-4449 .- 1399-0047. ; 62:10, s. 1196-1207
-
Tidskriftsartikel (refereegranskat)abstract
- The Structural Proteomics In Europe (SPINE) programme is aimed at the development and implementation of high-throughput technologies for the efficient structure determination of proteins of biomedical importance, such as those of bacterial and viral pathogens linked to human health. Despite the challenging nature of some of these targets, 175 novel pathogen protein structures (approximately 220 including complexes) have been determined to date. Here the impact of several technologies on the structural determination of proteins from human pathogens is illustrated with selected examples, including the parallel expression of multiple constructs, the use of standardized refolding protocols and optimized crystallization screens.
|
|
| 4. |
|
|
| 5. |
- Bolling-Sternevald, Elisabeth, et al.
(författare)
-
Effect of Profound Acid Suppression in Functional Dyspepsia : a Double-Blind, Randomized, Placebo-Controlled Trial
- 2002
-
Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 37:12, s. 1395-1402
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Functional dyspepsia (FD) is defined as persistent or recurrent pain/discomfort centred in the upper abdomen, where no structural explanation for the symptoms is found. The role of drug treatment remains controversial. The aim in this study was to evaluate the effect of omeprazole 20 mg twice daily (b.i.d) and to test methods for symptom assessment.Methods: 197 patients fulfilling the criteria for FD were randomly allocated to double-blind treatment with omeprazole 20 mg b.i.d ( n = 100) or placebo ( n = 97) for 14 days. Patients with a known gastrointestinal disorder or with main symptoms indicating gastro-oesophageal reflux disease or irritable bowel syndrome were excluded. Helicobacter pylori testing and 24-h intra-oesophageal 24-h pH-metry were performed before randomization. The patients recorded dyspeptic symptoms on diary cards.Results: A stringent endpoint, 'complete symptom relief on the last day of treatment', was the primary efficacy variable. For the APT cohort, this was achieved in 29.0% and 17.7% on omeprazole and placebo, respectively (95% CI of difference (11.3%): -0.4%-23.0%, P = 0.057). Similar figures in the PP cohort were 31.0% and 15.5%, respectively (95% CI of difference (15.5%): 3.2%-27.7%, P = 0.018). The benefit of omeprazole in the PP cohort was confirmed by secondary endpoints such as, no dyspeptic symptoms on the last 2 days of treatment and overall treatment response. H. pylori status and the level of oesophageal acid exposure did not significantly influence the response to therapy.Conclusion: A subset of patients with FD will respond to therapy with omeprazole.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Palma Medina, LM, et al.
(författare)
-
Targeted plasma proteomics reveals signatures discriminating COVID-19 from sepsis with pneumonia
- 2023
-
Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X. ; 24:1, s. 62-
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundCOVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features.MethodsWe measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients.ResultsWe identified a core response to infection consisting of 42 proteins altered in both COVID-19 and sepsis, although higher levels of cytokine storm-associated proteins were evident in sepsis. Furthermore, microbiologic etiology and clinical endotypes were linked to unique signatures. Finally, through machine learning, we identified biomarkers, such as TRIM21, PTN and CASP8, that accurately differentiated COVID-19 from CAP-sepsis with higher accuracy than standard clinical markers.ConclusionsThis study extends the understanding of host responses underlying sepsis and COVID-19, indicating varying disease mechanisms with unique signatures. These diagnostic and severity signatures are candidates for the development of personalized management of COVID-19 and sepsis.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
- Unge, Mikael, et al.
(författare)
-
Electron traps in polyethylene due to water
- 2022
-
Ingår i: ICD 2022 - IEEE 2022 4th International Conference on Dielectrics. - : Institute of Electrical and Electronics Engineers (IEEE). ; , s. 210-213
-
Konferensbidrag (refereegranskat)abstract
- Electron traps in polyethylene (PE) origin from water has been calculated using density functional theory. Atomistic structure has been simulated using molecular dynamics (MD) and used to calculate the electronic structure. Densities comparable with experimentally determined values are obtained. Both single water molecules and cluster of water molecules are considered. For a single water molecule both electron and hole states are within the bands from PE. The electron state is close to the conduction band minima (CBM) and may coincide with the CBM depending on the local atomic density. The absence of electron traps due to water is contradictory to previous simulation results but can be explained by atomic density and relaxation of conduction states of PE. Systems with 10 water molecules relaxed to two pentamers in the MD simulations. Calculation of trap levels of the pentamers result in trap levels in the order of 0.1-0.3 eV.
|
|
| 17. |
- Vrana, Nihal Engin, et al.
(författare)
-
From 3D printing to 3D bioprinting : the material properties of polymeric material and its derived bioink for achieving tissue specific architectures
- 2022
-
Ingår i: Cell and Tissue Banking. - : Springer Nature. - 1389-9333 .- 1573-6814. ; 23:3, s. 417-440
-
Forskningsöversikt (refereegranskat)abstract
- The application of 3D printing technologies fields for biological tissues, organs, and cells in the context of medical and biotechnology applications requires a significant amount of innovation in a narrow printability range. 3D bioprinting is one such way of addressing critical design challenges in tissue engineering. In a more general sense, 3D printing has become essential in customized implant designing, faithful reproduction of microenvironmental niches, sustainable development of implants, in the capacity to address issues of effective cellular integration, and long-term stability of the cellular constructs in tissue engineering. This review covers various aspects of 3D bioprinting, describes the current state-of-the-art solutions for all aforementioned critical issues, and includes various illustrative representations of technologies supporting the development of phases of 3D bioprinting. It also demonstrates several bio-inks and their properties crucial for being used for 3D printing applications. The review focus on bringing together different examples and current trends in tissue engineering applications, including bone, cartilage, muscles, neuron, skin, esophagus, trachea, tympanic membrane, cornea, blood vessel, immune system, and tumor models utilizing 3D printing technology and to provide an outlook of the future potentials and barriers.
|
|
| 18. |
|
|
| 19. |
- Bollati, Michela, et al.
(författare)
-
Structure and functionality in flavivirus NS-proteins : perspectives for drug design
- 2010
-
Ingår i: Antiviral Research. - : Elsevier BV. - 0166-3542 .- 1872-9096. ; 87:2, s. 125-148
-
Forskningsöversikt (refereegranskat)abstract
- Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded RNA genome. Besides yellow fever virus, a landmark case in the history of virology, members of the Flavivirus genus, such as West Nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. Additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. Nevertheless, up to few years ago flaviviruses were considered low interest candidates for drug design. At the start of the European Union VIZIER Project, in 2004, just two crystal structures of protein domains from the flaviviral replication machinery were known. Such pioneering studies, however, indicated the flaviviral replication complex as a promising target for the development of antiviral compounds. Here we review structural and functional aspects emerging from the characterization of two main components (NS3 and NS5 proteins) of the flavivirus replication complex. Most of the reviewed results were achieved within the European Union VIZIER Project, and cover topics that span from viral genomics to structural biology and inhibition mechanisms. The ultimate aim of the reported approaches is to shed light on the design and development of antiviral drug leads.
|
|
| 20. |
- Granqvist, P, et al.
(författare)
-
Sensed presence and mystical experiences are predicted by suggestibility, not by the application of transcranial weak complex magnetic fields
- 2005
-
Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940. ; 379:1, s. 1-6
-
Tidskriftsartikel (refereegranskat)abstract
- Transcranial magnetic stimulation (TMS) with weak (micro Tesla) complex waveform fields have been claimed to evoke the sensed presence of a sentient being in up to 80% in the general population. These findings have had a questionable neurophysiological foundation as the fields are approximately six orders of magnitude weaker than ordinary TMS fields. Also, no independent replication has been reported. To replicate and extend previous findings, we performed a double-blind experiment (N = 89), with a sham-field control group. Personality characteristics indicating suggestibility (absorption, signs of abnormal temporal lobe activity, and a "new age"-life-style orientation) were used as predictors. Sensed presence, mystical, and other somatosensory experiences previously reported from the magnetic field stimulation were outcome measures. We found no evidence for any effects of the magnetic fields, neither in the entire group, nor in individuals high in suggestibility. Because the personality characteristics significantly predicted outcomes, suggestibility may account for previously reported effects. Our results strongly question the earlier claims of experiential effects of weak magnetic fields.
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
- Lowder, M, et al.
(författare)
-
Effect of starvation and the viable-but-nonculturable state on green fluorescent protein (GFP) fluorescence in GFP-tagged Pseudomonas fluorescens A506
- 2000
-
Ingår i: Applied and Environmental Microbiology. - 0099-2240 .- 1098-5336. ; 66:8, s. 3160-3165
-
Tidskriftsartikel (refereegranskat)abstract
- The green fluorescent protein (GFP) gene, gfp, of the jellyfish Aequorea victoria is being used as a reporter system for gene expression and as a marker for tracking prokaryotes and eukaryotes. Cells that have been genetically altered with the gfp gene produce a protein that fluoresces when it is excited by UV light. This unique phenotype allows gth-tagged cells to be specifically monitored by nondestructive means, In this study we determined whether a gfp-tagged strain of Pseudomonas fluorescens continued to fluoresce under conditions under which the cells were starved, viable but nonculturable (VBNC), or dead. Epifluorescent microscopy, flow cytometry, and spectrofluorometry were used to measure fluorescence intensity in starved, VBNC, and dead or dying cells. Results obtained by using how cytometry indicated that microcosms containing VBNC cells, which were obtained by incubation under stress conditions (starvation at 37.5 degrees C), fluoresced at an intensity that mas at least 80% of the intensity of nonstressed cultures, Similarly, microcosms containing starved cells incubated at 5 and 30 degrees C had fluorescence intensities that were 90 to 110% of the intensity of nonstressed cells. VBNC cells remained fluorescent during the entire 6-month incubation period. in addition, cells starved at 5 or 30 degrees C remained fluorescent for at least 11 months. Treatment of the cells with UV light or incubation at 39 or 50 degrees C resulted in a loss of GFP from the cells. There was a strong correlation between cell death and leakage of GFP from the cells, although the extent of leakage varied depending on the treatment, Most dead cells were not GFP fluorescent, but a small proportion of the dead cells retained some GFP at a lower concentration than the concentration in live cells, Our results suggest that gfp-tagged cells remain fluorescent following starvation and entry into the VBNC state but that fluorescence is lost when the cells die, presumably because membrane integrity is lost.
|
|
| 25. |
- Mahalingam, A. Kannan, et al.
(författare)
-
HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol : Improved Antiviral Activity in Cells
- 2010
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:2, s. 607-615
-
Tidskriftsartikel (refereegranskat)abstract
- By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
- Rahman, A, et al.
(författare)
-
Fresh tympanic membrane perforations heal without significant loss of strength
- 2005
-
Ingår i: Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. - : Ovid Technologies (Wolters Kluwer Health). - 1531-7129. ; 26:6, s. 1100-1106
-
Tidskriftsartikel (refereegranskat)
|
|
| 30. |
- Rasmussen, E, et al.
(författare)
-
An abnormal chest radiograph
- 1998
-
Ingår i: Journal of cardiothoracic and vascular anesthesia. - : Elsevier BV. - 1053-0770. ; 12:1, s. 118-119
-
Tidskriftsartikel (refereegranskat)
|
|
| 31. |
- Unge, A, et al.
(författare)
-
Monitoring population size, activity, and distribution of gfp-luxAB-tagged Pseudomonas fluorescens SBW25 during colonization of wheat
- 2001
-
Ingår i: Microbial Ecology. - : Springer Science and Business Media LLC. - 0095-3628 .- 1432-184X. ; 41:4, s. 290-300
-
Tidskriftsartikel (refereegranskat)abstract
- Increasingly, focus has been directed towards the use of microorganisms as biological control agents to combat fungal disease, as an alternative to chemical fungicides. Pseudomonas fluorescens SBW25 is one bacterial strain that has been demonstrated to promote plant growth by biocontrol of pathogenic fungi. To understand the mode of action of this bacterium, information regarding its localization and metabolic activity on plants is important. In this study, a gfp/luxAB-tagged derivative of P. fluorescens SBW25, expressing the green fluorescent protein (GFP) and bacterial luciferase, was monitored during colonization of wheat starting from seed inoculation. Since bacterial luciferase is dependent on cellular energy reserves for phenotypic expression, metabolically active cells were detected using this marker. In contrast, the stable GFP fluorescence phenotype was used to detect the cells independently of their metabolic status. The combination of these two markers enabled P. fluorescens SBW25 cells to be monitored on wheat plants to determine their specific location and metabolic activity. Studies on homogenized wheat plant parts demonstrated that the seed was the preferred location of P. fluorescens SBW25 during the 65-day time period studied, but the leaves and roots were also colonized. Interestingly, the bacteria were also found to be metabolically active on all plant parts examined. In situ localization of P. fluorescens SBW25 using a combination of different microscopic techniques confirmed the preference for the cells to colonize specific regions of the seed. We speculate that the colonization pattern of P. fluorescens SBW25 can be linked to the mechanism of protection of plants from fungal infection.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
- Unge, Peter, et al.
(författare)
-
Does Omeprazole Improve Antimicrobial Therapy Directed Towards Gastric Campylobacter Pylori in Patients with Antral Gastritis? : A Pilot Study
- 1989
-
Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 24:s167, s. 49-54
-
Tidskriftsartikel (refereegranskat)abstract
- This double-blind pilot study has been undertaken in order to investigate the effect of amoxicillin and pronounced suppression of gastric acid secretion on mucosal colonisation with Campylobacter pylori (CP). Twentyfour CP-positive patients were included in the study and assigned to 14 days of treatment in either one of the following three therapy groups: Group 1: Omeprazole 40 mgo.m. + Amoxicillin 750 mgb.i.d (9pat); Group 2: Omeprazole 40 mg o.m. (8 pat); Group 3: Amoxicillin 750 mg b.i.d (7 pat).Gastroscopy with biopsy for culture and histology was performed pre-entry, at cessation of therapy and four weeks later. In the group receiving omeprazole and amoxicillin in combination 5 out of 8 patients were negative for CP four weeks after stopping treatment, while in the amoxicillin and the omeprazole groups respectively one (1/7) and none (0/8) were negative. Except for one patient who was withdrawn because of severe diarrhoea, only minor adverse effects occurred.
|
|
| 35. |
- Ursby, Thomas, et al.
(författare)
-
BioMAX the first macromolecular crystallography beamline at MAX IV Laboratory
- 2020
-
Ingår i: Journal of Synchrotron Radiation. - Chichester : Wiley-Blackwell. - 0909-0495 .- 1600-5775. ; 27, s. 1415-1429
-
Tidskriftsartikel (refereegranskat)abstract
- BioMAX is the first macromolecular crystallography beamline at the MAX IV Laboratory 3 GeV storage ring, which is the first operational multi-bend achromat storage ring. Due to the low-emittance storage ring, BioMAX has a parallel, high-intensity X-ray beam, even when focused down to 20 μm × 5 μm using the bendable focusing mirrors. The beam is tunable in the energy range 5-25 keV using the in-vacuum undulator and the horizontally deflecting double-crystal monochromator. BioMAX is equipped with an MD3 diffractometer, an ISARA high-capacity sample changer and an EIGER 16M hybrid pixel detector. Data collection at BioMAX is controlled using the newly developed MXCuBE3 graphical user interface, and sample tracking is handled by ISPyB. The computing infrastructure includes data storage and processing both at MAX IV and the Lund University supercomputing center LUNARC. With state-of-the-art instrumentation, a high degree of automation, a user-friendly control system interface and remote operation, BioMAX provides an excellent facility for most macromolecular crystallography experiments. Serial crystallography using either a high-viscosity extruder injector or the MD3 as a fixed-target scanner is already implemented. The serial crystallography activities at MAX IV Laboratory will be further developed at the microfocus beamline MicroMAX, when it comes into operation in 2022. MicroMAX will have a 1 μm × 1 μm beam focus and a flux up to 1015 photons s with main applications in serial crystallography, room-temperature structure determinations and time-resolved experiments.
|
|
| 36. |
- Wu, Xiongyu, et al.
(författare)
-
Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
- 2012
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:6, s. 2724-2736
-
Tidskriftsartikel (refereegranskat)abstract
- In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).
|
|
