Das Adapterprotein Grb2 in B- und T-Lymphozyten der Maus

Growth factor receptor bound protein 2 (Grb2) is a small, ubiquitously expressed and strongly conserved adapterprotein of 25-30 kDa. It contains one central Src homology 2 (SH2) and two neighboring Src homology 3 (SH3) domains and has no catalytic activity. Adapter proteins transmit and modulate proximal signals from receptors to distal functions. B-cell specific Grb2-/- mice show reduced B cell numbers in the periphery. Grb2 does not influence apoptosis of peripheral B cells but it is crucial for B cell development which explains the reduced B cell numbers. B-cell specific Grb2-/- mice show a block in B cell development which starts in immature B cells of the bone marrow but is most distinct in transitional B cells of the spleen. Grb2 forces the expression of genes that are upregulated in transitional B cells and are related to PI3K signaling. This implies that impaired PI3K signaling is a reason for the block in B cell development. Grb2 binds directly to the immunoglobulin tail tyrosine binding site of the IgG and IgE B-cell receptor in vitro which enhances B-cell receptor signaling. The transfer of defined numbers of IgG memory B-cells in recipient mice that are immunized afterwards to reactivate the IgG memory cells shows that Grb2 enhances the memory response of B cells in vivo and in a B-cell intrinsic fashion. This effect is independent of T-cell help. Grb2 enhances the memory response B cell intrinsically which is probably related to its binding to the immunoglobulin tail tyrosine binding site of the IgG B-cell receptor. It has previously been shown that Grb2 has crucial functions in positive and negative selection of T cells. Grb2fl/fl Lckcretg mice where Grb2 is deleted early in development show a drastically reduced number of T cells in the periphery. If Grb2 is deleted at a later point in development at the CD4+CD8+ stage (Grb2fl/fl CD4cretg mice) the reduction of T cells in the periphery is much weaker. T cell specific Grb2-/- mice show a less severe course of disease in an autoimmune encephalomyelitis model (EAE). Without Grb2 less TH1 and TH17 cells develop that elevate EAE severity whereas more regulatory T-cells develop that inhibit EAE. This seems to be related to a reduced activation potential of Grb2-/- T cells through antigen presenting cells. Therefore Grb2 is a positive factor for the development of TH1 and TH17 cells but a negative factor for the development of regulatory T cells in EAE. Mechanistically Grb2 also elevates the production of IL-6 which influences the ratio of TH17 and regulatory T cells and more proinflammatory TH17 T cells develop. In summary Grb2 has crucial and non redundant functions in lymphocyte development and in the effector functions of lymphocytes.Das Adapterprotein growth factor receptor bound protein 2 (Grb2) ist ein kleines, hoch konserviertes Protein von 25-30 kDa und verfügt über eine zentrale Src homology 2 (SH2) und zwei flankierende Src homology 3 (SH3) Domänen. Grb2 besitzt keine katalytische Funktion, sondern trägt dazu bei proximale, rezeptorvermittelte Signale weiterzuleiten und zu modulieren. B-Zell spezifische Grb2-/- Mäuse zeigen eine verringerte B-Zellzahl in der Peripherie. Grb2 hat keinen Einfluss auf die Apoptose von peripheren B-Zellen, sondern ist entscheidend in der B-Zell Entwicklung, was die reduzierten B-Zell Zahlen erklärt. B-Zell spezifische Grb2-/- Mäuse haben einen Block in der B-Zell Entwicklung, der in den unreifen B-Zellen im Knochenmark beginnt, aber in den transitionalen B-Zellen der Milz am deutlichsten wird. Grb2 wirkt fördernd auf Gene, die in transitionalen B-Zellen hoch reguliert werden und mit der PI3K Signalleitung in Verbindung stehen. Dies lässt vermuten, dass die PI3K Signalleitung am B-Zell Block beteiligt ist. Grb2 bindet in vitro direkt an die immunoglobulin tail tyrosine (ITT) Bindestelle im IgG- und IgE- B-Zell Rezeptor (BZR) und verstärkt so das BZR Signal. Durch den Transfer einer definierten Zahl an IgG Gedächtniszellen und einer erneuten Immunisierung der Empfängertiere zur Reaktivierung der Gedächtnis B-Zellen wurde gezeigt, dass Grb2 die Gedächtnisantwort auch in vivo zellintrinsisch fördert. Dieser Effekt ist unabhängig von T-Zell Hilfe. Der positive B-Zell intrinsiche Effekt von Grb2 auf die Gedächtnisantwort hängt vermutlich mit einer Bindung an die immunoglobulin tail tyrosine (ITT) Bindestelle im IgG BZR zusammen. Vorausgegangene Studien haben gezeigt, dass Grb2 in T-Zellen eine wichtige Rolle in der positiven und negativen Selektion von T-Zellen spielt. Grb2fl/fl Lckcretg Mäuse, die Grb2 früh in der T-Zell Entwicklung deletieren, haben eine drastisch reduzierte Zahl an T-Zellen in der Peripherie. Eine spätere Deletion von Grb2 in CD4+CD8+ T-Zellen des Thymus (Grb2fl/fl CD4cretg Mäuse) führt zu einer milderen Reduktion der T-Zellen in der Peripherie. T-Zell spezifische Grb2-/- Mäuse weisen einen milderen Krankheitsverlauf im autoimmunen Enzephalomyelitis Modell (EAE) auf als wildtyp Mäuse. Durch das fehlende Grb2 entwickeln sich weniger TH1 und TH17 Zellen, welche die EAE fördern, während mehr regulatorische T-Zellen gebildet werden, die inhibierend auf die Krankheit wirken. Dies hängt wahrscheinlich mit einer reduzierten Aktivierbarkeit der Grb2-/- T-Zellen durch antigenproduzierende Zellen zusammen. Damit ist Grb2 ein positiver Faktor für die Entwicklung von TH1 und TH17 Zellen und ein negativer Faktor für die Entwicklung von T-reg Zellen in der EAE. Mechanistisch fördert Grb2 die Produktion von IL-6 und könnte so das Verhältnis von TH17 zu regulatorischen T-Zellen zu Gunsten der proinflammatorischen TH17 T-Zellen verschieben. Zusammengefasst hat Grb2 wichtige, nicht redundante Funktionen bei der Entwicklung von Lymphozyten und der Funktion von Effektorlymphozyten

Exercise Training in Children and Adolescents with Cystic Fibrosis: Theory into Practice

Physical activity and exercise training play an important role in the clinical management of patients with cystic fibrosis (CF). Exercise training is more common and recognized as an essential part of rehabilitation programmes and overall CF care. Regular exercise training is associated with improved aerobic and anaerobic capacity, higher pulmonary function, and enhanced airway mucus clearance. Furthermore, patients with higher aerobic fitness have an improved survival. Aerobic and anaerobic training may have different effects, while the combination of both have been reported to be beneficial in CF. However, exercise training remains underutilised and not always incorporated into routine CF management. We provide an update on aerobic and anaerobic responses to exercise and general training recommendations in children and adolescents with CF. We propose that an active lifestyle and exercise training are an efficacious part of regular CF patient management

Expression of the Plasma Cell Transcriptional Regulator Blimp-1 by Dark Zone Germinal Center B Cells During Periods of Proliferation

Long-lived plasma cells (PCs) develop in germinal centers (GCs) by the differentiation of affinity matured B cells. Antibody affinity maturation involves iterative rounds of somatic hypermutation in dark zones (DZs) and selection in light zones (LZs), however the details of where, when and how PC commitment occurs are not well-understood. Fate bifurcation at the time of selection is one possibility, with the very highest affinity GC B cells differentiating as an alternative to DZ re-entry. However, how this model fits with a need to also retain these clones in the response is not clear. Here, we show that subsets of bona fide DZ cells express the plasma cell master regulator Blimp-1 at low levels during periods of proliferation. Ex vivo culture experiments demonstrate that these cells are not yet committed to plasma cell differentiation but that they may be sensitized to go down that route. Contrary to models in which T cells directly select GC B cells to begin expressing Blimp-1, we found that expression of this transcriptional regulator occurred even when follicular helper T cells were ablated. We speculate that Blimp-1 may be induced during proliferation in the DZ, and that as such single selected cells might give rise to both GC and post-GC progeny

CONFLITOS DE AGÊNCIA E OS DESAFIOS DA GOVERNANÇA EM UMA UNIVERSIDADADE COMUNITÁRIA

As organizações de ensino superior têm sido reconhecidas em função de sua complexidade, seja na consecução de seus meios, seja na aferição da performance das atividades fim. Nesta linha, as Instituições Comunitárias de Ensino Superior - ICES, tem um grau de dificuldade elevado visto que tem como propósito medidas de impacto social nas comunidades e não guardam vínculos com a performance financeiro para além de sua sustentabilidade direta. Surgem ainda os desdobramentos de elementos que tem sido discutidos pela Teoria da Agência e que buscam, na Governança Organizacional, mecanismos que possam realizar a coordenação de interesses entre as diversas instâncias de principal/agente das ICES. O estudo realiza um debate das características típicas das ICES a partir dos conflitos de agência e dos desdobramentos dos interesses conflitantes e as vezes difusos de diversos atores que a compõe. O estudo, de caráter qualitativo, debateu o tema a partir de um consistente respaldo teórico e de um conjunto de entrevistas realizadas junto a gestores de uma universidade comunitária gaúcha. O artigo levanta um conjunto de possíveis desdobramentos deste quadro e busca constituir um conjunto de subsídios para que estas organizações possam enfrentar este quadro sem que para isto tenham que abrir mão de seus fundamentos constitutivos ou até mesmo descaracterizar-se

GESTIÓN HUMANIZADA EN TIEMPOS DE PANDEMIA: IMPACTOS Y CONTRIBUCIONES AL COOPERATIVISMO

Objetivo: Este artigo tem como objetivo evidenciar como a gestão humanizada impacta e contribui para o cooperativismo, em tempos de pandemia. Metodologia: Como metodologia, utilizou-se pesquisa bibliográfica, documental e entrevistas com gestores e colaboradores de quatro cooperativas do Rio Grande do Sul. Resultados: Os resultados evidenciaram que as estratégias e práticas cooperativistas implementadas nas cooperativas analisadas, são contempladas por todos os pilares da gestão humanizada, sendo que a tecnologia acaba assumindo papel fundamental nesta inter-relação e neste contexto. O estudo permite concluir que a gestão humanizada se constitui como estratégia valorativa e de sustentabilidade, minimizando as consequências negativas geradas pela pandemia, impactando e contribuindo positivamente para o desenvolvimento das cooperativas analisadas e de seus agentes envolvidos, do mercado do cooperativismo e de toda a sociedade. Contribuições: Apesar do estudo apresentar limitações quanto ao tamanho da amostra e restringir-se a um segmento institucional e contexto específicos, são destacadas suas contribuições teóricas, práticas e sociais quanto a abordagens relacionadas à Covid-19 e demais pandemias, à gestão humanizada e ao cooperativismo e quanto à forma com que tais abordagens impactam nos atores, processos e dinâmicas de desenvolvimento organizacional e territorial, em tempos de complexidade, mudanças e incertezas. Ressalta-se, também, a relevância do estudo para acadêmicos, docentes e teóricos das áreas da gestão, saúde e desenvolvimento, e para gestores e demais stakeholders envolvidos nas dinâmicas de atuação e desenvolvimento do cooperativismo. Originalidade: O estudo preenche, ainda, uma lacuna de investigação quanto à demanda de estudos sobre as contribuições da gestão humanizada para o cooperativismo e sobre esta inter-relação no contexto da pandemia.Objective: This article aims to show how humanized management impacts and contributes to cooperativism, in times of pandemic. Methodology: As a methodology, bibliographic, documentary research and interviews with managers and employees of four cooperatives in Rio Grande do Sul were used. Results: The results showed that the cooperative strategies and practices implemented in the analyzed cooperatives are covered by all pillars of humanized management, being that technology ends up assuming a fundamental role in this interrelation and in this context. The study concludes that humanized management is a value and sustainability strategy, minimizing the negative consequences generated by the pandemic, impacting and positively contributing to the development of the analyzed cooperatives and their agents involved, the cooperative market and the whole of society. Contributions: Although the study has limitations in terms of sample size and is restricted to a specific institutional segment and context, its theoretical, practical and social contributions regarding approaches related to Covid-19 and other pandemics, humanized management and cooperativism are highlighted. as to the way in which these approaches impact on the actors, processes and dynamics of organizational and territorial development, in times of complexity, changes and uncertainties. The relevance of the study for academics, teachers and theorists in the areas of management, health and development, and for managers and other stakeholders involved in the dynamics of action and development of cooperatives is also emphasized. Originality: The study also fills a research gap regarding the demand for studies on the contributions of humanized management to cooperativism and on this interrelation in the context of the pandemic.Objetivo: Este artículo tiene como objetivo mostrar cómo la gestión humanizada impacta y contribuye al cooperativismo, en tiempos de pandemia. Metodología: Como metodología se utilizó investigación bibliográfica, documental y entrevistas a gerentes y empleados de cuatro cooperativas en Rio Grande do Sul. Resultados: Los resultados mostraron que las estrategias y prácticas cooperativas implementadas en las cooperativas analizadas están cubiertas por todos los pilares de la gestión humanizada, siendo que la tecnología acaba asumiendo un papel fundamental en esta interrelación y en este contexto. El estudio permite concluir que la gestión humanizada es una estrategia de valor y sostenibilidad, minimizando las consecuencias negativas generadas por la pandemia, impactando y contribuyendo positivamente al desarrollo de las cooperativas analizadas y sus agentes involucrados, el mercado cooperativo y el conjunto de la sociedad. Contribuciones: Aunque el estudio tiene limitaciones en cuanto al tamaño de la muestra y se restringe a un segmento y contexto institucional específico, sus aportes teóricos, prácticos y sociales en cuanto a enfoques relacionados con Covid-19 y otras pandemias, gestión humanizada y cooperativismo y en cuanto a la forma en que estas Los enfoques impactan en los actores, procesos y dinámicas del desarrollo organizacional y territorial, en tiempos de complejidad, cambios e incertidumbres. También se enfatiza la relevancia del estudio para académicos, docentes y teóricos de las áreas de gestión, salud y desarrollo, y para gerentes y otros actores involucrados en la dinámica de acción y desarrollo de las cooperativas. Originalidad: El estudio también llena un vacío de investigación sobre la demanda de estudios sobre las contribuciones de la gestión humanizada al cooperativismo y sobre esta interrelación en el contexto de la pandemia

An EigenValue Stabilization Technique for Immersed Boundary Finite Element Methods in Explicit Dynamics

The application of immersed boundary methods in static analyses is often impeded by poorly cut elements (small cut elements problem), leading to ill-conditioned linear systems of equations and stability problems. While these concerns may not be paramount in explicit dynamics, a substantial reduction in the critical time step size based on the smallest volume fraction $\chi$ of a cut element is observed. This reduction can be so drastic that it renders explicit time integration schemes impractical. To tackle this challenge, we propose the use of a dedicated eigenvalue stabilization (EVS) technique. The EVS-technique serves a dual purpose. Beyond merely improving the condition number of system matrices, it plays a pivotal role in extending the critical time increment, effectively broadening the stability region in explicit dynamics. As a result, our approach enables robust and efficient analyses of high-frequency transient problems using immersed boundary methods. A key advantage of the stabilization method lies in the fact that only element-level operations are required. This is accomplished by computing all eigenvalues of the element matrices and subsequently introducing a stabilization term that mitigates the adverse effects of cutting. Notably, the stabilization of the mass matrix $\mathbf{M}_\mathrm{c}$ of cut elements -- especially for high polynomial orders $p$ of the shape functions -- leads to a significant raise in the critical time step size $\Delta t_\mathrm{cr}$. To demonstrate the efficacy of our technique, we present two specifically selected dynamic benchmark examples related to wave propagation analysis, where an explicit time integration scheme must be employed to leverage the increase in the critical time step size.Comment: 45 pages, 25 figure

Epidermal γδ T cells sense precancerous cellular dysregulation and initiate immune responses

Hyperplasia associated with a loss of tissue homeostasis can induce DNA replication stress, leading to precancerous dysregulation. Epidermal γδ T cells reside in the primary barrier that protects against diverse environmental insults; however, the functions of these T cells in tissue surveillance are not completely understood. In mice with inducible Notch1 inactivation in keratinocytes that causes epidermal hyperplasia, epidermal γδ T cells sensed stressed keratinocytes and migrated into the cutaneous draining lymph nodes. Simultaneous induction of β-galactosidase (β-Gal) as a putative antigen expressed in the process of precancerous dysregulation and Notch1 ablation in the epidermis resulted in elevated β-Gal-specific IgG2a production. Epidermal γδ T cells were found to have the capacity to express chemokine (C-C motif) receptor 7 and migrate into the lymph nodes. Cutaneous draining lymph node cells in Notch1-inactivated mice expressed high levels of IFN-γ upon anti-CD3 plus anti-CD28 stimulation. Furthermore, induced expression of β-Gal in mice that lacked epidermal γδ T cells failed to induce anti-β-Gal IgG. These results suggest that epidermal γδ T cells play an essential role in the initiation process of epidermal antigen-specific humoral immune responses and demonstrate the importance of epidermal γδ T cells in sensing precancerous dysregulation and activating adaptive immunit

MEDICIÓN DE LA EFICIENCIA EN LAS BIBLIOTECAS DE UNIVERSIDADES PÚBLICAS ESPAÑOLAS

Este trabajo se analizó la eficiencia de las bibliotecas de las universidades públicas españolas aplicando la técnica de programación lineal de Data Envelopment Analysis (DEA), tomando como significado de eficiencia en la utilización de los recursos asignados a cada una de ellas. Para el desarrollo del modelo DEA se utiliza el programa EMS. En este artículo se pretende calcular en una muestra de 24 bibliotecas universitarias españolas, para los periodos 2014 y 2015 la eficiencia en relación con los inputs y outputs seleccionados. La aplicación de la técnica DEA sobre las bibliotecas universitarias ha permitido establecer el listado, así como el ranking de universidades. La proporción de bibliotecas eficientes al 100% en términos globales es mayor para el año 2015 que para el año 2014. Madrid, Barcelona y Sevilla (ciudades con una población superior a 500.000 habitantes y con más de una biblioteca pública universitaria a disposición de los usuarios) cuentan con bibliotecas eficientes al 100% tanto para 2014 como para 2015

Brain metastasis from urachal carcinoma: the importance of locally aggressive treatment

We present the case of a 52 years old woman who developed multiple brain metastasis after cystectomy with anterior exenteration and chemotherapy. She received whole-brain radiotherapy with 20 gray in 5 sessions. On magnetic resonance imaging 8 weeks after radiotherapy she showed a regression of some lesions while others responded only partially. This case-report and a review of the literature show the importance of aggressive local treatment in patients with brain metastasis from urachal carcinoma