| 1. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
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Enhanement of amyloid fibril binding by ring expansion of thiazolino fused 2-pyridone peptidomimetics
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Thiazolino fused 2-pyridones undergo thiazoline ring opening by reaction with 2-nitrobenzyl bromide through thi- oether attack, and base promoted fragmentation of the resulting sulfonium ions. Subsequent deprotonation of the benzylic carbon and intramolecular 1,4-addition leads to ring closure, generating dihydrothiazine fused 2-pyridones by net ring expansion of the thiazoline ring. Application of the ring expansion procedure to the pyridine and pyrimidine fused thiazolino 2-pyridones provided compounds with enhanced fibril binding activity.
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| 2. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
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Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
- 2020
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:21, s. 14174-14189
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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.
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| 3. |
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| 4. |
- Adolfsson, Göran, 1981, et al.
(författare)
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Direct observation of lateral carrier diffusion in ridge waveguide InGaNAs lasers
- 2009
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Ingår i: IEEE Photonics Technology Letters. - 1041-1135 .- 1941-0174. ; 21:134, s. 134-136
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Tidskriftsartikel (refereegranskat)abstract
- We present results from measurements of the subthreshold lateral spontaneous emission profile in 1.3-mu m wavelength ridge waveguide InGaNAs quantum-well lasers using a scanning near-field optical microscopy technique. The measurements reveal the presence of significant lateral carrier diffusion which has a profound effect on the temperature dependence of the threshold current. This effect is frequently omitted when the characteristic temperature of the threshold current is considered.
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| 5. |
- Adolfsson, Göran, 1981, et al.
(författare)
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Effects of Lateral Diffusion on the Temperature Sensitivity of the Threshold Current for 1.3 um Double Quantum-Well GaInNAs/GaAs Lasers
- 2008
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Ingår i: IEEE Journal of Quantum Electronics. ; 44:7, s. 607-616
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Tidskriftsartikel (refereegranskat)abstract
- We present an experimental and theoretical investigationof the temperature dependence of the threshold current fordouble quantum well GaInNAs–GaAs lasers in the temperaturerange 10 C–110 C. Pulsed measurements of the threshold current have been performed on broad and narrow ridge wave guide(RWG) lasers. The narrow RWG lasers exhibit high characteristic temperatures (T0)of 200 K up to a critical temperature (Tc), above which T0 is reduced by approximately a factor of 2. The T0-values for broad RWG lasers are significantly lower than those for the narrow RWG lasers, with characteristic temperatures on the order of 100 (60) K below (above). Numerical simulations, using a model that accounts for lateral diffusion effects, show good agreement with experimental data and reveal that a weakly temperature dependent lateral diffusion current dominates thethreshold current for narrow RWG lasers.
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| 6. |
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| 7. |
- Adolfsson, Göran, 1981, et al.
(författare)
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Realization of spectrally engineered semiconductor Fabry-Perot lasers with narrow geometrical tolerances
- 2011
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 109:9, s. 093112-
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Tidskriftsartikel (refereegranskat)abstract
- Spectrally engineered semiconductor Fabry-Perot laser resonators are designed to enhance the optical feedback for selected longitudinal modes, which thereby require less gain for lasing. This is achieved by introducing refractive index perturbations along the length of the resonator. However,the physical realization of these resonators is a challenge because of very narrow tolerances; in particular the need for precise positioning of the end facets of the resonator in relation to the perturbations, and the excess propagation loss associated with the perturbations, has been a majorconcern. We report on a method to achieve high-quality end facet mirrors enabling precise positioning relative to the perturbations, the latter which are realized as lateral corrugations of the waveguide. Measurements show that the mirror quality is comparable to that of cleaved mirrorsand that the additional loss introduced by the perturbations adds
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| 8. |
- Adolfsson, Göran, 1981, et al.
(författare)
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Spectral engineering of semiconductor Fabry–Perot laser cavities in the weakly and strongly perturbed regimes
- 2010
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Ingår i: Journal of the Optical Society of America B: Optical Physics. - 1520-8540 .- 0740-3224. ; 27:1, s. 118-127
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Tidskriftsartikel (refereegranskat)abstract
- By inserting index perturbations at certain positions along a semiconductor Fabry–Perot laser cavity thethreshold gain for one or several of the longitudinal cavity modes can be selectively lowered to facilitate, e.g.,single-mode or two-color operation. Previous design methods were limited to a fairly small number of perturbations,leading to only weakly perturbed cavities and thus a limited freedom in tailoring the spectral propertiesof the laser. In our approach we fully account for all multiple-reflection events and use a search spacethat permits any distribution of the locations and lengths of the perturbations. We are therefore able to designcavities with almost arbitrary spectral properties with very low threshold gain values for, e.g., the lasingmodes of a two-color cavity. Constraining the design by reducing the geometrical freedom, which can be used toincrease the smallest feature size to simplify fabrication, we seamlessly approach the weakly perturbed regimewhile maintaining much of the freedom for spectral engineering.
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| 9. |
- Adolfsson, Jörgen
(författare)
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Expression and role of the cytokine tyrosine kinase receptor flt3 in early hematopoiesis
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mature blood cells are crucial for life, but they have a short lifetime and thus have to be replaced. These mature blood cells are produced by lineage restricted progenitors, which themselves are generated by rare multipotent hematopoietic stem cells (HSCs) in a highly dynamic process called hematopoiesis. In addition to the ability of HSCs to generate all blood cell lineages, they possess the unique property of self-renewal, a process in which a HSC, during a cell division generate at least one daughter cell identical to the parental cell. The maintenance and regulation of HSCs and earliest stages of lineage development are partly controlled by soluble and membrane bound regulators called cytokines. The focus in this thesis has been on the cytokine tyrosine kinase receptor flt3 and its ligand and their role in regulating HSCs and the earliest progenitors in adult murine bone marrow (BM). Earlier studies had implicated a role for flt3 and its ligand in the maintenance of HSCs. When studying mice with targeted deletion of the flt3 ligand (FL), we failed to find any role of flt3 and its ligand in HSC regulation. However, the generation of the common lymphoid progenitor (CLP) and earliest stages of B- and T cell development were severely affected, but not myeloid progenitors or later stages of lymphoid development. Based on flt3 expression, we subfractionated the Lin(-)Sca-1(+)c-kit(+) (LSK) stem cell pool in mouse bone marrow. In contrast to LSKflt3- cells, which sustained multilineage long-term reconstitution, LSKflt3+ cells generated only short-term lymphoid dominated reconstitution when injected into lethally ablated recipients. We also demonstrated the hierarchical relationship at the earliest stages of hematopoiesis, in that LSKflt3- HSCs generate LSKflt3+ cells, which generate the CLP but not the LSKflt3- cells. In the classical model of the hematopoietic hierarchy, the first lineage commitment step of HSCs results in a strict separation into distinct lymphoid and myeloid pathways, generating the recently identified CLP and the common myeloid progenitor (CMP). However, in sharp contrast to LSKflt3-, cells which could generate all blood cell lineages, LSK cells expressing flt3 could not generate megakaryocytes or erythroid cells. Thus, these finding together with the above mentioned relationship between the LSKflt3-, LSKflt3+ and CLP do not support the classical hematopoietic hierarchy model depicting the first lineage commitment generating a strict separation of lymphoid and myeloid pathways. The LSK population contains all LT-HSC activity. However, this population is not homogenous neither in phenotype or function and it has been proposed to contain at least two populations, one with long-term reconstitution (LTR) potential and one with short-term reconstitution potential. Based on the expression of CD34 and flt3 within the adult LSK stem cell pool we were able to subfractionate short-term hematopoietic stem cells (ST-HSC) from the LT-HSCs. In contrast to the LSKCD34-flt3- and LSKCD34+flt3+ cells, the LSKCD34+flt3- is highly enriched for CFU-S activity and capable of rescuing lethally irradiated recipients, fulfilling the criteria of ST-HSCs.
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| 10. |
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| 11. |
- Adolfsson, Jörgen, et al.
(författare)
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Identification of Flt3(+) lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment
- 2005
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Ingår i: Cell. - : Elsevier (Cell Press). - 0092-8674 .- 1097-4172. ; 121:2, s. 295-306
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Tidskriftsartikel (refereegranskat)abstract
- All blood cell lineages derive from a common hematopoietic stem cell (HSC). The current model implicates that the first lineage commitment step of adult pluripotent HSCs results in a strict separation into common lymphoid and common myeloid precursors. We present evidence for a population of cells which, although sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. Cells in the Lin-Sca-1+c-kit+ HSC compartment coexpressing high levels of the tyrosine kinase receptor Flt3 sustain granulocyte, monocyte, and B and T cell potentials but in contrast to Lin-Sca-1(+)ckit(+)Flt3(-) HSCs fail to produce significant erythroid and megakaryocytic progeny. This distinct lineage restriction site is accompanied by downregulation of genes for regulators of erythroid and megakaryocyte development. In agreement with representing a lymphoid primed progenitor, Lin(-)Sca-l(+)c-kit(+)CD34(+)Flt3(+) cells display upregulated IL-7 receptor gene expression. Based on these observations, we propose a revised road map for adult blood lineage development.
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| 12. |
- Adolfsson, Jörgen, et al.
(författare)
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Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity
- 2001
-
Ingår i: Immunity. - 1074-7613. ; 15:4, s. 659-669
-
Tidskriftsartikel (refereegranskat)abstract
- Flt3 has emerged as a potential regulator of hematopoietic stem cells (HSC). Sixty percent of cells in the mouse marrow Lin(-)Sca1(+)c-kit(+) HSC pool expressed flt3. Although single cell cloning showed comparable high proliferative, myeloid, B, and T cell potentials of Lin(-)Sca1(+)c-kit(+)flt3(+) and Lin(-)Sca1(+)c-kit(+)flt3(-) cells, only Lin(-)Sca1(+)c-kit(+)flt3(-) cells supported sustained multilineage reconstitution. In striking contrast, Lin(-)Sca1(+)c-kit(+)flt3(+) cells rapidly and efficiently reconstituted B and T lymphopoiesis, whereas myeloid reconstitution was exclusively short term. Unlike c-kit, activation of flt3 failed to support survival of HSC, whereas only flt3 mediated survival of Lin(-)Sca1(+)c-kit(+)flt3(+) reconstituting cells. Phenotypic and functional analysis support that Lin(-)Sca1(+)c-kit(+)flt3(+) cells are progenitors for the common lymphoid progenitor. Thus, upregulation of flt3 expression on Lin(-)Sca1(+)c-kit(+) HSC cells is accompanied by loss of self-renewal capacity but sustained lymphoid-restricted reconstitution potential.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Bharate, Jaideep B., et al.
(författare)
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K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
- 2021
-
Ingår i: Organic and biomolecular chemistry. - : The Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 19:44, s. 9758-9772
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Tidskriftsartikel (refereegranskat)abstract
- We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.
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| 18. |
- Bryder, David, et al.
(författare)
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Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation
- 2001
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 194:7, s. 941-952
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Tidskriftsartikel (refereegranskat)abstract
- Multipotent self-renewing hematopoietic stem cells (HSCs) are responsible for reconstitution of all blood cell lineages. Whereas growth stimulatory cytokines have been demonstrated to promote HSC self-renewal, the potential role of negative regulators remains elusive. Receptors for tumor necrosis factor (TNF) and Fas ligand have been implicated as regulators of steady-state hematopoiesis, and if overexpressed mediate bone marrow failure. However, it has been proposed that hematopoietic progenitors rather than stem cells might be targeted by Fas activation. Here, murine Lin(-)Sca1(+)c-kit(+) stem cells revealed little or no constitutive expression of Fas and failed to respond to an agonistic anti-Fas antibody. However, if induced to undergo self-renewal in the presence of TNF-alpha, the entire short and long-term repopulating HSC pool acquired Fas expression at high levels and concomitant activation of Fas suppressed in vitro growth of Lin(-)Sca1(+)c-kit(+) cells cultured at the single cell level. Moreover, Lin(-)Sca1(+)c-kit(+) stem cells undergoing self-renewal divisions in vitro were severely and irreversibly compromised in their short- and long-term multilineage reconstituting ability if activated by TNF-alpha or through Fas, providing the first evidence for negative regulators of HSC self-renewal.
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| 19. |
- Dumitrescu, Mihail, et al.
(författare)
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10 Gb/s uncooled dilute nitride optical transmitters operating at 1300 nm
- 2009
-
Ingår i: 2009 Conference on Optical Fiber Communication, OFC 2009; San Diego, CA; United States; 22 March 2009 through 26 March 2009. - Washington, D.C. : OSA. - 9781557528650
-
Konferensbidrag (refereegranskat)abstract
- Dilute-nitride lasers with record performances have been used to build uncooled transceivers and failure free 10 Gb/s optical transmission was achieved over 815 m of multimode Corning InfiniCor fiber under the LRM standard.
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| 20. |
- Frigyesi, Ildiko, et al.
(författare)
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Robust isolation of malignant plasma cells in multiple myeloma.
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 123:9, s. 1336-1340
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Tidskriftsartikel (refereegranskat)abstract
- Molecular characterization of malignant plasma cells is increasingly important for diagnostic and therapeutic stratification in multiple myeloma (MM). However, the malignant plasma cells represent a relatively small subset of bone marrow cells, and need to be enriched prior to analysis. Currently, the cell surface marker CD138 (SDC1) is used for this enrichment, but has an important limitation in that its expression decreases rapidly after sampling. Seeking alternatives to CD138, we performed a computational screen for myeloma plasma cell markers and evaluated seven candidates systematically. Our results conclusively show that the markers CD319 (SLAMF7/CS1) and CD269 (TNFRSF17/BCMA) are considerably more robust than CD138, and enable isolation of myeloma plasma cells under more diverse conditions, including in samples that have been delayed or frozen. Our results form the basis of improved procedures for characterizing cases of multiple myeloma in clinical practice.
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| 21. |
- Hultberg, Jonas, et al.
(författare)
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In-depth immune profiling reveals advanced B- and T-cell differentiation to be associated with Th1-driven immune dysregulation in common variable immunodeficiency
- 2023
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Ingår i: Clinical Immunology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1521-6616 .- 1521-7035. ; 257
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Tidskriftsartikel (refereegranskat)abstract
- Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by low levels of an-tibodies. In addition to infections, many patients also suffer from T-helper 1-driven immune dysregulation, which is associated with increased mortality. The aim of this study was to perform in-depth characterization of the T and the B cell compartments in a well-defined cohort of patients affected by CVID and correlate the findings to the level of clinical immune dysregulation. We used mass cytometry, targeted proteomics, flow cytometry and functional assays to delineate the immunological phenotype of 15 CVID-affected patients with different levels of immune dysregulation. Unbiased clustering of T cell mass cytometry data correlated with CVID-related immune dysregulation and plasma protein profiles. Expanded CXCR3+ T-bet-expressing B cells correlated with effector memory CD4+ T cell clusters, and increased plasma levels of CXCR3-ligands. Our findings indicate an interplay between B cells and T cells in CVID-related immune dysregulation and provide a better understanding of the underlying pathological mechanisms.
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| 22. |
- Lind, Alexander, et al.
(författare)
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Immunocyte single cell analysis of vaccine-induced narcolepsy
- 2021
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Ingår i: European Journal of Immunology. - : John Wiley & Sons. - 0014-2980 .- 1521-4141. ; 51:1, s. 247-249
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Increased incidence of narcolepsy type 1 (NT1) was observed following Pandemrix®-vaccination, initiated as a preventive measure against the 2009 Influenza pandemic. Here, single cell analysis was conducted to suggest a lower number of CD8+CD27+ T cells among these patients. These findings provide understanding into the autoimmune pathogenesis of NT1.
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| 23. |
- Mehmeti-Ajradini, Meliha, et al.
(författare)
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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
- 2020
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Ingår i: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 3:11
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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| 24. |
- Månsson, Robert, et al.
(författare)
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Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors
- 2007
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 26:4, s. 407-419
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies implicated the existence of adult lymphoid-primed multipotent progenitors (LMPPs) with little or no megakaryocyte-erythroid potential, questioning common myeloid and lymphoid progenitors as obligate intermediates in hematopoietic stem cell (HSC) lineage commitment. However, the existence of LMPPs remains contentious. Herein, global and single-cell analyses revealed a hierarchical organization of transcriptional lineage programs, with downregulation of megakaryocyte-erythroid genes from HSCs to LMPPs, sustained granulocyte-monocyte priming, and upregulation of common lymphoid (but not B and T cell-specific) genes. These biological and molecular relationships, implicating almost mutual exclusion of megakaryocyte-erythroid and lymphoid pathways, are established already in fetal hematopoiesis, as evidenced by existence of LMPPs in fetal liver. The identification of LMPPs and hierarchically ordered transcriptional activation and downregulation of distinct lineage programs is compatible with a model for HSC lineage commitment in which the probability for undergoing different lineage commitment fates changes gradually when progressing from HSCs to LMPPs.
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| 25. |
- Rörby, Emma, et al.
(författare)
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Multiplexed single-cell mass cytometry reveals distinct inhibitory effects on intracellular phosphoproteins by midostaurin in combination with chemotherapy in AML cells
- 2021
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Ingår i: Experimental Hematology & Oncology. - : BMC. - 2162-3619. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundFms-related tyrosine kinase 3 (FLT3) receptor serves as a prognostic marker and therapeutic target in acute myeloid leukemia (AML). Approximately one-third of AML patients carry mutation in FLT3, associated with unfavourable prognosis and high relapse rate. The multitargeted kinase inhibitor midostaurin (PKC412) in combination with standard chemotherapy (daunorubicin and cytarabine) was recently shown to increase overall survival of AML patients. For that reason, PKC412 has been approved for treatment of AML patients with FLT3-mutation. PKC412 synergizes with standard chemotherapy, but the mechanism involved is not fully understood and the risk of relapse is still highly problematic.MethodsBy utilizing the unique nature of mass cytometry for single cell multiparameter analysis, we have explored the proteomic effect and intracellular signaling response in individual leukemic cells with internal tandem duplication of FLT3 (FLT3-ITD) after midostaurin treatment in combination with daunorubicin or cytarabine.ResultsWe have identified a synergistic inhibition of intracellular signaling proteins after PKC412 treatment in combination with daunorubicin. In contrast, cytarabine antagonized phosphorylation inhibition of PKC412. Moreover, we found elevated levels of FLT3 surface expression after cytarabine treatment. Interestingly, the surface localization of FLT3 receptor increased in vivo on the blast cell population of two AML patients during day 3 of induction therapy (daunorubicin; once/day from day 1-3 and cytarabine; twice/day from day 1-7). We found FLT3 receptor expression to correlate with intracellular cytarabine (AraC) response. AML cell line cultured with AraC with or without PKC412 had an antagonizing phosphorylation inhibition of pAKT (p=0.042 and 0.0261, respectively) and pERK1/2 (0.0134 and 0.0096, respectively) in FLT3(high) compared to FLT3(low) expressing cell populations.ConclusionsOur study provides insights into how conventional chemotherapy affects protein phosphorylation of vital signaling proteins in human leukemia cells. The results presented here support further investigation of novel strategies to treat FLT3-mutated AML patients with PKC412 in combination with chemotherapy agents and the potential development of novel treatment strategies.
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| 26. |
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| 27. |
- Singh, Pardeep, et al.
(författare)
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Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones
- 2019
-
Ingår i: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 21, s. 6946-6950
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Tidskriftsartikel (refereegranskat)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 substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.
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| 28. |
- Sitnicka Quinn, Ewa, et al.
(författare)
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Key Role of flt3 Ligand in Regulation of the Common Lymphoid Progenitor but Not in Maintenance of the Hematopoietic Stem Cell Pool.
- 2002
-
Ingår i: Immunity. - 1074-7613. ; 17:4, s. 463-472
-
Tidskriftsartikel (refereegranskat)abstract
- The first lineage commitment step of hematopoietic stem cells (HSC) results in separation into distinct lymphoid and myeloid differentiation pathways, reflected in the generation of common lymphoid and myeloid progenitors (CLP and CMP, respectively). In this report we present the first evidence for a nonredundant regulator of this process, in that adult mice deficient in expression of the flt3 ligand (FL) have severely (10-fold) reduced levels of the CLP, accompanied by reductions in the earliest identifiable B and T cell progenitors. In contrast, CMP and HSC are unaffected in FL-deficient mice. Noteworthy, CLP express high levels of both the flt3 receptor and ligand, indicating a potential autocrine role of FL in regulation of the earliest lymphoid commitment step from HSC.
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| 29. |
- Tyagi, Mohit, et al.
(författare)
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Functionalization of Thiazolino fused 2-Pyridones by thiazoline ring opening and closing : Identification of new Amyloid Binding Heterocycles
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Reaction of thiazolino fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generate N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via an intramolecular [2 + 2] cycloaddition between in situ generated allene and the α,β-unsaturated carbonyl moiety. This method enabled the synthesis of a variety of cyclobutane and thiazolino fused 2-pyridones, which were tested for α-synuclein binding activity. Most of the bioactive thiazolino fused 2-pyridones tolerated this transformation and in addition provided an exocyclic alkene as a handle for tuning bioactivity.
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| 30. |
- Tyagi, Mohit, et al.
(författare)
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Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones
- 2021
-
Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 86:23, s. 16582-16592
-
Tidskriftsartikel (refereegranskat)abstract
- Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.
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| 31. |
- Yang, Liping, et al.
(författare)
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Identification of Lin(-)Sca1(+)kit(+)CD34(+)Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients
- 2005
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Ingår i: Blood. - Washington : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 105:7, s. 2717-2723
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Tidskriftsartikel (refereegranskat)abstract
- In clinical bone marrow transplantation, the severe cytopenias induced by bone marrow ablation translate into high risks of developing fatal infections and bleedings, until transplanted hematopoietic stem and progenitor cells have replaced sufficient myeloerythroid offspring. Although adult long-term hematopoietic stem cells (LT-HSCs) are absolutely required and at the single-cell level sufficient for sustained reconstitution of all blood cell lineages, they have been suggested to be less efficient at rapidly reconstituting the hematopoietic system and rescuing myeloablated recipients. Such a function has been proposed to rather be mediated by less well-defined short-term hematopoietic stem cells (ST-HSCs). Herein, we demonstrate that Lin(-)Sca1(+)kit(hi)CD34+ short-term reconstituting cells contain 2 phenotypically and functionally distinct subpopulations: Lin(-)Sca1(+)kit(hi)CD34(+)flt3- cells fulfilling all criteria of ST-HSCs, capable of rapidly reconstituting myelopoiesis, rescuing myeloablated mice, and generating Lin(-)Sca1(+)kit(hi)CD34(+)flt3+ cells, responsible primarily for rapid lymphoid reconstitution. Representing the first commitment steps from Lin(-)Sca1(+)kit(hi) CD34(-)flt3- LT-HSCs, their identification will greatly facilitate delineation of regulatory pathways controlling HSC fate decisions and identification of human ST-HSCs responsible for rapid reconstitution following HSC transplantations.
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