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Wind energy is an important renewable energy source. Rotor main bearings are critical components of wind turbines since a faulty main bearing leads to downtime and high repair costs. Operational expenditures amount to 32% of wind energy costs. The use of plain bearings as main bearings can potentially reduce these costs. Plain bearings with segmented sliding elements can be repaired up-tower without dismantling the drivetrain, as damaged segments can be exchanged individually. One such segmented plain bearing design is the conical plain bearing design called FlexPad. For the FlexPad, proof of concept was achieved for the 1 MW range during previous studies. Modern wind turbines—especially for offshore deployment—have increased in size significantly compared with their predecessors. The goal of current studies is to transfer the FlexPad design towards a main bearing unit at a market relevant scale of 8.5 MW. In this work, the identified scaling challenges are presented. A FlexPad model scaled to the 8.5 MW range is presented to illustrate the challenges. The bearing load components, such as radial forces and torque, increase on different scales with increasing rotor size leading to changed load characteristics with increasing size. Increased rotor weight and bearing diameters result in an increase in the breakaway torque required to start turbine rotation. This breakaway torque can exceed the torque generated by the turbine at starting wind speeds. The generally increased loads necessitate stiffer sliding segments leading to the increased weight of the segments, which hampers the ability to easily exchange segments.

Lotte F Westbroek,1 Margot Klijnsma,1 Philippe Salomé,2 Lidewij M Sekhuis,1,3 Emiel Rolink,3 Erny Korsmit,4 Huib AM Kerstjens1,3 On behalf of the LAN COPD Care Pathway Study Group1Department of Pulmonary Diseases, University of Groningen, and University Medical Center Groningen, Groningen Research Institute for Asthma and COPD GRIAC, Groningen, The Netherlands; 2General practitioner, private practice, IJsselstein, The Netherlands; 3Lung Alliance Netherlands (LAN), Amersfoort, The Netherlands; 4Bravis Hospital, The Netherlands and Senior Advisor Healthcare Networking at Korsmit Zorgadvies, Bergen Op Zoom, The NetherlandsCorrespondence: Huib AM KerstjensDepartment of Pulmonary Diseases, University Medical Center Groningen, Room S3.131 (AA11), Postbox 30.001, Groningen 9700RB, The NetherlandsTel +31 50 361-0280Fax +31 50 36 19320Email h.a.m.kerstjens@umcg.nlBackground: Many patients with chronic obstructive pulmonary disease (COPD) experience exacerbations of symptoms, leading to a large burden on patients and the health system and costs to society. To address this burden, a 25% reduction in number of hospitalization days for COPD exacerbations was recently declared a national goal in the Netherlands, to be achieved in 5 years.Methods: A national care pathway was designed following an established managed clinical pathway setup, which involved prior national surveys and the identification of ten key elements. The concept was discussed, made locally applicable, and finally tested in eight regions containing eleven hospitals and surrounding primary-care groups in a prospective cohort study. All patients were followed for 1 year, starting at hospitalization.Results: In total, 752 patients gave informed consent and participated (mean age 70 years, 58% female). Of these, 120 (16%) died within a year. The median length of index hospitalization was 5 days, and 43% had at least one rehospitalization within 1 year (range 0– 8). There was a 19.4% reduction in number of total hospitalization days, without a decrease in health-related quality of life or perceived quality of care. Elements that contributed significantly to the reduction were contact in the first week after hospitalization, and during the year of follow-up pharmacological and nonpharmacological smoking-cessation guidance, checks on inhalation technique, and discussion of lung-attack plan.Discussion: With concerted action between patients and health workers in the hospital and in the community, a large reduction in number of hospitalization days can be achieved. The program was quite demanding for both patients and health workers. In our subsequent national implementation plan after this pilot study, we have named the major contributors to success and advocate the stepwise introduction of the elements in light of feasibility.Keywords: COPD, National Action Program, managed-care pathway, hospitalization

Analysis of the cell surface proteome (surfaceome) is essential for cell classification but is technically challenging. Here the authors miniaturize and automate the Cell Surface Capture method to increase sensitivity, reproducibility and throughput, and use it to create population-specific surfaceome maps of developing mouse B cells.

Cynthia Hallensleben,1,* Sanne van Luenen,1,* Emiel Rolink,2 Hans C Ossebaard,3,4 Niels H Chavannes11Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands; 2Lung Alliance Netherlands, Amersfoort, the Netherlands; 3National Health Care Institute, Diemen, the Netherlands; 4Department of Medical Informatics, Amsterdam UMC, Amsterdam, the Netherlands*These authors contributed equally to this workBackground: In the Netherlands, almost 600,000 people had chronic obstructive pulmonary disease (COPD) in 2017. This decreases quality of life for many and each year, COPD leads to approximately 6,800 deaths and about one billion health care expenditures. It is expected that eHealth may improve access to care and reduce costs. However, there is no conclusive scientific evidence available of the added value of eHealth in COPD care. We conducted a scoping review into the use of eHealth in Dutch COPD care. The aim of the research was to provide an overview of all eHealth applications used in Dutch COPD care and to assess these applications on a number of relevant criteria.Methods: In order to make an overview of all eHealth applications aimed at COPD patients in the Netherlands, literature was searched in the electronic databases PubMed and Google Scholar. In addition, Dutch health care websites were searched for applications that have been evaluated for effectiveness and reliability. The identified eHealth applications were assessed according to five relevant quality criteria, eg, whether research has been conducted on the effectiveness.Results: Thirteen health care programs and patient platforms in COPD care have been found that use eHealth. In addition, 13 self-care and informative websites and 15 mobile apps were found that are available to citizens and patients. Five of 13 care programs and patient platforms were found to be effective in improving quality of life or reducing hospital admissions in small pilot studies. The effectiveness of these and the other eHealth applications should be established in larger studies in the future.Discussion: More research into the effectiveness of eHealth applications for COPD patients is needed. We recommend to develop a nationwide open source platform where well-evaluated eHealth applications can be showcased for patients and health care providers to improve COPD care.Keywords: COPD, eHealth, care programs, scoping review

Testosterone deficiency is associated with autoimmunity and increased B cell numbers, but the underlying mechanism is unclear. Here the authors show that testosterone may modulate the production of B cell survival factor BAFF by fibroblastic reticular cells via regulation of splenic neurotransmitter levels.

BAFF is an important cytokine for B cell survival, and is a therapeutic target for autoimmune disorders. Here the authors show that a 'flap' region of BAFF converts BAFFR binding events into survival signals and, with structural data, that this ‘flap’ differentially modulates binding of drugs such as belimumab or atacicept.

Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokines. IL-7 is an important survival and proliferation factor for B cell progenitors, whereas FL acts on several early developmental stages, prior to B cell commitment. We have generated mice constitutively over-expressing both IL-7 and FL. These double transgenic mice develop splenomegaly and lymphadenopathy characterized by tremendously enlarged lymph nodes even in young animals. Lymphoid, myeloid and dendritic cell numbers are increased compared to mice over-expressing either of the two cytokines alone and the effect on their expansion is synergistic, rather than additive. B cell progenitors, early progenitors with myeloid and lymphoid potential (EPLM), common lymphoid progenitors (CLP) and lineage−, Sca1+, kit+ (LSK) cells are all increased not only in the bone marrow but also in peripheral blood, spleen and even lymph nodes. When transplanted into irradiated wild-type mice, lymph node cells show long-term multilineage reconstitution, further confirming the presence of functional hematopoietic progenitors therein. Our double transgenic mouse model shows that sustained and combined over-expression of IL-7 and FL leads to a massive expansion of most bone marrow hematopoietic progenitors and to their associated presence in peripheral lymphoid organs where they reside and potentially differentiate further, thus leading to the synergistic increase in mature lymphoid and myeloid cell numbers. The present study provides further in vivo evidence for the concerted action of IL-7 and FL on lymphopoiesis and suggests that extramedullary niches, including those in lymph nodes, can support the survival and maintenance of hematopoietic progenitors that under physiological conditions develop exclusively in the bone marrow.

Murine chronic graft-versus-host-disease (cGvHD) induced by injection of parental lymphocytes into F1 hybrids results in a disease similar to systemic lupus erythematosus. Here, we have used DBA/2 T cell injection into (C57BL/6 × DBA/2)F1 (BDF1) mice as a model system to test the prophylactic and therapeutic effects of interleukin-2 (IL-2)/anti-IL-2 immune complexes on the course of cGvHD. Our findings demonstrate that pretreatment with Treg inducing JES6/IL-2 complexes render BDF1 mice largely resistant to induction of cGvHD, whereas pretreatment with CD8+ T cell/NK cell inducing S4B6/IL-2 complexes results in a more severe cGvHD. In contrast, treatment with JES6/IL-2 complexes 4 weeks after induction had no beneficial effect on disease symptoms. However, similar treatment with S4B6/IL-2 complexes led to a significant amelioration of the disease. This therapeutic effect seems to be mediated by donor CD8+ T cells. The fact that a much stronger cGvHD is induced in BDF1 mice depleted of donor CD8+ T cells strongly supports this conclusion. The contrasting effects of the two different IL-2 complexes are likely due to different mechanisms.

Summary: B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner. : Smulski et al. report that the B cell survival receptor BAFFR undergoes ligand-induced shedding but only in cells co-expressing a second receptor for BAFF called TACI. BAFFR shedding can be performed by ADAM10 in circulating B cells or by ADAM17 in germinal center B cells and limits BAFF-mediated survival signals. Keywords: B cell, BAFF-receptor, BAFFR, TACI, ADAM10, ADAM17, metalloprotease, processing, ectodomain shedding, germinal center, survival

For successful bone marrow transplantation (BMT), a preconditioning regime involving chemo and radiotherapy is used that results in DNA damage to both hematopoietic and stromal elements. Following radiation exposure, it is well recognized that a single wave of host-derived thymocytes reconstitutes the irradiated thymus, with donor-derived thymocytes appearing about 7 days post BMT. Our previous studies have demonstrated that, in the presence of donor hematopoietic cells lacking T lineage potential, these host-derived thymocytes are able to generate a polyclonal cohort of functionally mature peripheral T cells numerically comprising ~25% of the peripheral T cell pool of euthymic mice. Importantly, we demonstrated that radioresistant CD44+ CD25+ CD117+ DN2 progenitors were responsible for this thymic auto-reconstitution. Until recently, the mechanisms underlying the radioresistance of DN2 progenitors were unknown. Herein, we have used the in vitro “Plastic Thymus” culture system to perform a detailed investigation of the mechanisms responsible for the high radioresistance of DN2 cells compared with radiosensitive hematopoietic stem cells. Our results indicate that several aspects of DN2 biology, such as (i) rapid DNA damage response (DDR) activation in response to ionizing radiation-induced DNA damage, (ii) efficient repair of DNA double-strand breaks, and (iii) induction of a protective G1/S checkpoint contribute to promoting DN2 cell survival post-irradiation. We have previously shown that hypoxia increases the radioresistance of bone marrow stromal cells in vitro, at least in part by enhancing their DNA double-strand break (DNA DSB) repair capacity. Since the thymus is also a hypoxic environment, we investigated the potential effects of hypoxia on the DDR of DN2 thymocytes. Finally, we demonstrate for the first time that de novo DN2 thymocytes are able to rapidly repair DNA DSBs following thymic irradiation in vivo.

The escape of anti-self B cells from tolerance mechanisms like clonal deletion, receptor editing, and anergy results in the production of autoantibodies, which is a hallmark of many autoimmune disorders. In this study, we demonstrate that both germline sequences and somatic mutations contribute to autospecificity of B cell clones. For this issue, we investigated the development of antinuclear autoantibodies (ANAs) and their repertoire in two different mouse models. First, in aging mice that were shown to gain several autoimmune features over time including ANAs. Second, in mice undergoing a chronic graft-versus-host disease (GVHD), thereby developing systemic lupus erythematosus-like symptoms. Detailed repertoire analysis revealed that somatic hypermutations (SHM) were present in all Vh and practically all Vl regions of ANAs generated in these two models. The ANA B cell repertoire in aging mice was restricted, dominated by clonally related Vh1-26/Vk4-74 antibodies. In the collection of GVHD-derived ANAs, the repertoire was less restricted, but the usage of the Vh1-26/Vk4-74 combination was still apparent. Germline conversion showed that the SHM in the 4-74 light chain are deterministic for autoreactivity. Detailed analysis revealed that antinuclear reactivity of these antibodies could be induced by a single amino acid substitution in the CDR1 of the Vk4-74. In both aging B6 and young GVHD mice, conversion of the somatic mutations in the Vh and Vl regions of non Vh1-26/Vk4-74 using antibodies showed that B cells with a germline-encoded V gene could also contribute to the ANA-reactive B cell repertoire. These findings indicate that two distinct pathways generate ANA-producing B cells in both model systems. In one pathway, they are generated by Vh1-26/Vk4-74 expressing B cells in the course of immune responses to an antigen that is neither a nuclear antigen nor any other self-antigen. In the other pathway, ANA-producing B cells are derived from progenitors in the bone marrow that express B cell receptors (BCRs), which bind to nuclear antigens and that escape tolerance induction, possibly as a result of crosslinking of their BCRs by multivalent determinants of nuclear antigens.