| 1. |
- Altincekic, Nadide, et al.
(författare)
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Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies
- 2024
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 19:2, s. 563-574
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Tidskriftsartikel (refereegranskat)abstract
- The main protease Mpro, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with Mpro. These investigations resulted in the four-armed compound 35b that binds directly to Mpro. 35b could be cocrystallized with Mpro revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.
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| 2. |
- Efe, Cumali, et al.
(författare)
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Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis
- 2018
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Ingår i: Digestive Diseases and Sciences. - : SPRINGER. - 0163-2116 .- 1573-2568. ; 63:5, s. 1348-1354
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Tidskriftsartikel (refereegranskat)abstract
- We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.
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| 3. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 4. |
- Ihalainen, Hannes, et al.
(författare)
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Certified MaxSAT Preprocessing
- 2024
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Ingår i: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). - 1611-3349 .- 0302-9743. ; 14739 LNAI, s. 396-418
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Konferensbidrag (refereegranskat)abstract
- Building on the progress in Boolean satisfiability (SAT) solving over the last decades, maximum satisfiability (MaxSAT) has become a viable approach for solving NP-hard optimization problems. However, ensuring correctness of MaxSAT solvers has remained a considerable concern. For SAT, this is largely a solved problem thanks to the use of proof logging, meaning that solvers emit machine-verifiable proofs to certify correctness. However, for MaxSAT, proof logging solvers have started being developed only very recently. Moreover, these nascent efforts have only targeted the core solving process, ignoring the preprocessing phase where input problem instances can be substantially reformulated before being passed on to the solver proper. In this work, we demonstrate how pseudo-Boolean proof logging can be used to certify the correctness of a wide range of modern MaxSAT preprocessing techniques. By combining and extending the VeriPB and CakePB tools, we provide formally verified end-to-end proof checking that the input and preprocessed output MaxSAT problem instances have the same optimal value. An extensive evaluation on applied MaxSAT benchmarks shows that our approach is feasible in practice.
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| 5. |
- Ramström, Therese, et al.
(författare)
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Spasticity-correcting surgery can have long-lasting effects
- 2023
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Ingår i: Lakartidningen. - 1652-7518. ; 120
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Tidskriftsartikel (refereegranskat)abstract
- Spasticity is a common secondary complication after injuries to the central nervous system (CNS). Spasticity may severely impair arm and hand function, and consequently, affect an individual's function, resulting in disabilities or limiting activities and participation. Today, there is conflicting evidence regarding the effectiveness of available spasticity treatments. The population of adults with spasticity problems due to a CNS injury is heterogenic. A multidisciplinary approach is essential in customizing treatment to individual needs. The planning of treatment should consider the remaining upper limb functions and the patient's potential to improveme. Spasticity-correcting surgery is an option that seems underutilized. This article describes a structured and standardized program for the preoperative assessment, the surgical technique and the postoperative rehabilitation of patients undergoing upper limb spasticity-correcting surgery.
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| 6. |
- Theissinger, Kathrin, et al.
(författare)
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How genomics can help biodiversity conservation
- 2023
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Ingår i: Trends in Genetics. - : Elsevier. - 0168-9525 .- 1362-4555. ; 39:7, s. 545-559
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Forskningsöversikt (refereegranskat)abstract
- The availability of public genomic resources can greatly assist biodiversity assessment, conservation, and restoration efforts by providing evidence for scientifically informed management decisions. Here we survey the main approaches and applications in biodiversity and conservation genomics, considering practical factors, such as cost, time, prerequisite skills, and current shortcomings of applications. Most approaches perform best in combination with reference genomes from the target species or closely related species. We review case studies to illustrate how reference genomes can facilitate biodiversity research and conservation across the tree of life. We conclude that the time is ripe to view reference genomes as fundamental resources and to integrate their use as a best practice in conservation genomics.
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