La geografia a la Universitat Autònoma de Barcelona : un projecte d'Enric Lluch (II)

S'ha complert mig segle d'ensenyament de la geografia a la UAB (de 1969 a 2019). Al present article se n'hi expliquen els primers vint anys, fins a completar el desenvolupament de la Llei de reforma universitària (LRU) a la nostra universitat, i s'hi dona a conèixer quin era l'equip acadèmic que va acompanyar Enric Lluch (1928-2012) en aquesta experiència. També s'hi introdueix la geografia que recollia els enfocaments innovadors que arribaven principalment de França, dels països anglosaxons i d'Itàlia, i s'hi mostra la formació docent i investigadora del professorat, a més del desenvolupament de les eines científiques que han fet possible l'assentament de la geografia a la UAB. Bàsicament, es tracta d'explicar-hi la recerca, els contactes internacionals, els laboratoris i la revista Documents d'Anàlisi Geogràfica, entre d'altres qüestions. A les conclusions s'hi valora l'esforç col·lectiu que ha fet possible que aquest procés hagi continuat amb èxit, tant a Bellaterra com a Girona.Se ha cumplido medio siglo de enseñanza de la geografía en la UAB (de 1969 a 2019). En el presente artículo se explican sus primeros veinte años hasta completar el desarrollo de la Ley de reforma universitaria (LRU) en nuestra universidad y se da a conocer cuál era el equipo académico que acompañó a Enric Lluch (1928-2012) en esta experiencia. Se introduce la geografía que recogía los enfoques innovadores que llegaban principalmente de Francia, de los países anglosajones y de Italia, y se muestra la formación docente e investigadora del profesorado, así como el desarrollo de las herramientas científicas que han hecho posible el asentamiento de la geografía en la UAB. Básicamente, se trata de contar la investigación, los contactos internacionales, los laboratorios y la revista Documents d'Anàlisi Geogràfica, entre otros aspectos. En las conclusiones se valora el esfuerzo colectivo que ha hecho posible que este proceso haya continuado con éxito, tanto en Bellaterra como en Girona.Cinquante ans d'enseignement de la Géographie à l'UAB (1969 à 2019) viennent d'être célébrés. Les 20 premières années sont présentées, jusqu'à l'achèvement du développement de la loi sur la réforme de l'université (LRU) à l'UAB, ainsi que l'équipe académique qui a accompagné Enric Lluch (1928-2012) dans cette expérience. On a introduit la géographie qui a rassemblé les approches novatrices venues principalement de la France, des pays anglo-saxons et de l'Italie. Dans cette deuxième partie, nous expliquons la formation des enseignants en matière d'enseignement et de recherche, ainsi que le développement des outils scientifiques qui ont permis l'établissement de la géographie à l'UAB. Il s'agit essentiellement de recherche, de contacts internationaux, de laboratoires et du journal Documents d'Anàlisi Geogràfica, entre autres. Dans les conclusions, l'effort collectif qui a permis à ce processus de se poursuivre avec succès, à Bellaterra comme à Girona, est valorisé.Geography has been taught at the Autonomous University of Barcelona (UAB) for 50 years (1969-2019). This paper explores the first 20 years of geography until the entry into force of the University Reform Law (LRU) at the UAB and the academic team that accompanied Enric Lluch (1928-2012) in this experience. The introduction of geography based on innovative approaches coming mainly from France, English-speaking countries and Italy is discussed. In this second part we also describe the teaching and research training of teachers, and the development of scientific tools that have made the establishment of geography in the UAB possible: basically, research, international contacts, laboratories and the Documents d'Anàlisi Geogràfica journal, among others. To conclude, the collective effort that has contributed to the success of this process both in Bellaterra and in Girona is examined

Results of a national UK physician reported survey of COVID-19 infection in patients with a myeloproliferative neoplasm

Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/50110000027

Binding Strength and Dynamics of Invariant Natural Killer Cell T Cell Receptor/CD1d-Glycosphingolipid Interaction on Living Cells by Single Molecule Force Spectroscopy*

Invariant natural killer T (iNKT) cells are a population of T lymphocytes that play an important role in regulating immunity to infection and tumors by recognizing endogenous and exogenous CD1d-bound lipid molecules. Using soluble iNKT T cell receptor (TCR) molecules, we applied single molecule force spectroscopy for the investigation of the iNKT TCR affinity for human CD1d molecules loaded with glycolipids differing in the length of the phytosphingosine chain using either recombinant CD1d molecules or lipid-pulsed THP1 cells. In both settings, the dissociation of the iNKT TCR from human CD1d molecules loaded with the lipid containing the longer phytosphingosine chain required higher unbinding forces compared with the shorter phytosphingosine lipid. Our findings are discussed in the context of previous results obtained by surface plasmon resonance measurements. We present new insights into the energy landscape and the kinetic rate constants of the iNKT TCR/human CD1d-glycosphingolipid interaction and emphasize the unique potential of single molecule force spectroscopy on living cells

Validation of clinical‐grade whole genome sequencing reproduces cytogenetic analysis and identifies mutational landscape in newly‐diagnosed multiple myeloma patients: A pilot study from the 100,000 Genomes Project

Abstract Multiple myeloma is characterized by chromosomal abnormalities and genetic variation, which may inform prognosis and guide treatment. This pilot study sought to examine the feasibility of incorporating Whole Genome Sequencing (WGS) alongside the routine laboratory evaluation of 14 patients with newly diagnosed multiple myeloma who had enrolled in the 100,000 Genomes Project. In all 14 cases, WGS data could be obtained in a timely fashion within existing clinical frameworks in a tertiary hospital setting. The data not only replicated standard‐of‐care FISH analysis of chromosomal abnormalities but also provided further chromosomal and molecular genetic insights that may influence patient management

Constitutively Active Lck Kinase in T Cells Drives Antigen Receptor Signal Transduction

T cell antigen receptor (TCR) and coreceptor ligation is thought to initiate signal transduction by inducing activation of the kinase Lck. Here we showed that catalytically active Lck was present in unstimulated naive T cells and thymocytes and was readily detectable in these cells in lymphoid organs. In naive T cells up to ∼40% of total Lck was constitutively activated, part of which was also phosphorylated on the C-terminal inhibitory site. Formation of activated Lck was independent of TCR and coreceptors but required Lck catalytic activity and its maintenance relied on monitoring by the HSP90-CDC37 chaperone complex to avoid degradation. The amount of activated Lck did not change after TCR and coreceptor engagement; however it determined the extent of TCR-ζ phosphorylation. Our findings suggest a dynamic regulation of Lck activity that can be promptly utilized to initiate T cell activation and have implications for signaling by other immune receptors

Design, Synthesis, and Functional Activity of Labeled CD1d Glycolipid Agonists

Invariant natural killer T cells (<i>i</i>NKT cells) are restricted by CD1d molecules and activated upon CD1d-mediated presentation of glycolipids to T cell receptors (TCRs) located on the surface of the cell. Because the cytokine response profile is governed by the structure of the glycolipid, we sought a method for labeling various glycolipids to study their in vivo behavior. The prototypical CD1d agonist, α-galactosyl ceramide (α-GalCer) <b>1</b>, instigates a powerful immune response and the generation of a wide range of cytokines when it is presented to <i>i</i>NKT cell TCRs by CD1d molecules. Analysis of crystal structures of the TCR−α-GalCer–CD1d ternary complex identified the α-methylene unit in the fatty acid side chain, and more specifically the <i>pro</i>-<i>S</i> hydrogen at this position, as a site for incorporating a label. We postulated that modifying the glycolipid in this way would exert a minimal impact on the TCR–glycolipid–CD1d ternary complex, allowing the labeled molecule to function as a good mimic for the CD1d agonist under investigation. To test this hypothesis, the synthesis of a biotinylated version of the CD1d agonist threitol ceramide (ThrCer) was targeted. Both diastereoisomers, epimeric at the label tethering site, were prepared, and functional experiments confirmed the importance of substituting the <i>pro</i>-<i>S</i>, and not the <i>pro</i>-<i>R</i>, hydrogen with the label for optimal activity. Significantly, functional experiments revealed that biotinylated ThrCer (<i>S</i>)-<b>10</b> displayed behavior comparable to that of ThrCer <b>5</b> itself and also confirmed that the biotin residue is available for streptavidin and antibiotin antibody recognition. A second CD1d agonist, namely α-GalCer C20:2 <b>4</b>, was modified in a similar way, this time with a fluorescent label. The labeled α-GalCer C20:2 analogue (<b>11</b>) again displayed functional behavior comparable to that of its unlabeled substrate, supporting the notion that the α-methylene unit in the fatty acid amide chain should be a suitable site for attaching a label to a range of CD1d agonists. The flexibility of the synthetic strategy, and late-stage incorporation of the label, opens up the possibility of using this labeling approach to study the in vivo behavior of a wide range of CD1d agonists

Design, Synthesis, and Functional Activity of Labeled CD1d Glycolipid Agonists

Invariant natural killer T cells (<i>i</i>NKT cells) are restricted by CD1d molecules and activated upon CD1d-mediated presentation of glycolipids to T cell receptors (TCRs) located on the surface of the cell. Because the cytokine response profile is governed by the structure of the glycolipid, we sought a method for labeling various glycolipids to study their in vivo behavior. The prototypical CD1d agonist, α-galactosyl ceramide (α-GalCer) <b>1</b>, instigates a powerful immune response and the generation of a wide range of cytokines when it is presented to <i>i</i>NKT cell TCRs by CD1d molecules. Analysis of crystal structures of the TCR−α-GalCer–CD1d ternary complex identified the α-methylene unit in the fatty acid side chain, and more specifically the <i>pro</i>-<i>S</i> hydrogen at this position, as a site for incorporating a label. We postulated that modifying the glycolipid in this way would exert a minimal impact on the TCR–glycolipid–CD1d ternary complex, allowing the labeled molecule to function as a good mimic for the CD1d agonist under investigation. To test this hypothesis, the synthesis of a biotinylated version of the CD1d agonist threitol ceramide (ThrCer) was targeted. Both diastereoisomers, epimeric at the label tethering site, were prepared, and functional experiments confirmed the importance of substituting the <i>pro</i>-<i>S</i>, and not the <i>pro</i>-<i>R</i>, hydrogen with the label for optimal activity. Significantly, functional experiments revealed that biotinylated ThrCer (<i>S</i>)-<b>10</b> displayed behavior comparable to that of ThrCer <b>5</b> itself and also confirmed that the biotin residue is available for streptavidin and antibiotin antibody recognition. A second CD1d agonist, namely α-GalCer C20:2 <b>4</b>, was modified in a similar way, this time with a fluorescent label. The labeled α-GalCer C20:2 analogue (<b>11</b>) again displayed functional behavior comparable to that of its unlabeled substrate, supporting the notion that the α-methylene unit in the fatty acid amide chain should be a suitable site for attaching a label to a range of CD1d agonists. The flexibility of the synthetic strategy, and late-stage incorporation of the label, opens up the possibility of using this labeling approach to study the in vivo behavior of a wide range of CD1d agonists

CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes

Invariant natural killer T cells (iNKT cells) are involved in the host defense against microbial infection. Although it is known that iNKT cells recognize glycolipids presented by CD1d, how and where they encounter antigen in vivo remains unclear. Here we used multiphoton microscopy to visualize the dynamics and activation of iNKT cells in lymph nodes. After antigen administration, iNKT cells became confined in a CD1d-dependent manner in close proximity to subcapsular sinus CD169(+) macrophages. These macrophages retained, internalized and presented lipid antigen and were required for iNKT cell activation, cytokine production and population expansion. Thus, CD169(+) macrophages can act as true antigen-presenting cells controlling early iNKT cell activation and favoring the fast initiation of immune responses