How and Why Do Students Use Learning Strategies? A Mixed Methods Study on Learning Strategies and Desirable Difficulties With Effective Strategy Users

In order to ensure long-term retention of information students must move from relying on surface-level approaches that are seemingly effective in the short-term to “building in” so called “desirable difficulties,” with the aim of achieving understanding and long-term retention of the subject matter. But how can this level of self-regulation be achieved by students when learning? Traditionally, research on learning strategy use is performed using self-report questionnaires. As this method is accompanied by several drawbacks, we chose a qualitative, in-depth approach to inquire about students' strategies and to investigate how students successfully self-regulate their learning. In order to paint a picture of effective learning strategy use, focus groups were organized in which previously identified, effectively self-regulating students (N = 26) were asked to explain how they approach their learning. Using a constructivist grounded theory methodology, a model was constructed describing how effective strategy users manage their learning. In this model, students are driven by a personal learning goal, adopting a predominantly qualitative, or quantitative approach to learning. While learning, students are continually engaged in active processing and self-monitoring. This process is guided by a constant balancing between adhering to established study habits, while maintaining a sufficient degree of flexibility to adapt to changes in the learning environment, assessment demands, and time limitations. Indeed, students reported using several strategies, some of which are traditionally regarded as “ineffective” (highlighting, rereading etc.). However, they used them in a way that fit their learning situation. Implications are discussed for the incorporation of desirable difficulties in higher education

Generation and characterization of CD1d-specific single-domain antibodies with distinct functional features

Ligation of the CD1d antigen-presenting molecule by monoclonal antibodies (mAbs) can trigger important biological functions. For therapeutic purposes camelid-derived variable domain of heavy-chain-only antibodies (VHH) have multiple advantages over mAbs because they are small, stable and have low immunogenicity. Here, we generated 21 human CD1d-specific VHH by immunizing Lama glama and subsequent phage display. Two clones induced maturation of dendritic cells, one clone induced early apoptosis in CD1d-expressing B lymphoblasts and multiple myeloma cells, and another clone blocked recognition of glycolipid-loaded CD1d by CD1d-restricted invariant natural killer T (iNKT) cells. In contrast to reported CD1d-specific mAbs, these CD1d-specific VHH have the unique characteristic that they induce specific and well-defined biological effects. This feature, combined with the above-indicated general advantages of VHH, make the CD1d-specific VHH generated here unique and useful tools to exploit both CD1d ligation as well as disruption of CD1d–iNKT interactions in the treatment of cancer or inflammatory disorders

Highly specific and potently activating Vγ9Vδ2-T cell specific nanobodies for diagnostic and therapeutic applications

Vγ9Vδ2-T cells constitute the predominant subset of γδ-T cells in human peripheral blood and have been shown to play an important role in antimicrobial and antitumor immune responses. Several efforts have been initiated to exploit these cells for cancer immunotherapy, e.g. by using phosphoantigens, adoptive cell transfer, and by a bispecific monoclonal antibody based approach. Here, we report the generation of a novel set of Vγ9Vδ2-T cell specific VHH (or nanobody). VHH have several advantages compared to conventional antibodies related to their small size, stability, ease of generating multispecific molecules and low immunogenicity. With high specificity and affinity, the anti-Vγ9Vδ2-T cell receptor VHHs are shown to be useful for FACS, MACS and immunocytochemistry. In addition, some VHH were found to specifically activate Vγ9Vδ2-T cells. Besides being of possible immunotherapeutic value, these single domain antibodies will be of great value in the further study of this important immune effector cell subset

Prevention of Vγ9Vδ2 T Cell Activation by a Vγ9Vδ2 TCR Nanobody

Vγ9Vδ2 T cell activation plays an important role in antitumor and antimicrobial immune responses. However, there are conditions in which Vγ9Vδ2 T cell activation can be considered inappropriate for the host. Patients treated with aminobisphosphonates for hypercalcemia or metastatic bone disease often present with a debilitating acute phase response as a result of Vγ9Vδ2 T cell activation. To date, no agents are available that can clinically inhibit Vγ9Vδ2 T cell activation. In this study, we describe the identification of a single domain Ab fragment directed to the TCR of Vγ9Vδ2 T cells with neutralizing properties. This variable domain of an H chain-only Ab (VHH or nanobody) significantly inhibited both phosphoantigen-dependent and -independent activation of Vγ9Vδ2 T cells and, importantly, strongly reduced the production of inflammatory cytokines upon stimulation with aminobisphosphonate-treated cells. Additionally, in silico modeling suggests that the neutralizing VHH binds the same residues on the Vγ9Vδ2 TCR as the Vγ9Vδ2 T cell Ag-presenting transmembrane protein butyrophilin 3A1, providing information on critical residues involved in this interaction. The neutralizing Vγ9Vδ2 TCR VHH identified in this study might provide a novel approach to inhibit the unintentional Vγ9Vδ2 T cell activation as a consequence of aminobisphosphonate administration

A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells

Though Vγ9Vδ2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vγ9Vδ2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vγ9Vδ2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vγ9Vδ2-T cells and EGFR induced potent Vγ9Vδ2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients

Percutaneous mitral valve repair preserves right ventricular function

Chronic mitral regurgitation (MR) often leads to diminished right ventricular (RV) function due to long-standing pressure and volume overload. Surgical intervention often adds to the preexisting RV dysfunction. Percutaneous mitral valve (MV) repair can reduce MR, but to what extent this affects the right ventricle is unknown. Consecutive patients scheduled for percutaneous MV repair using the MitraClip system underwent transthoracic echocardiography at baseline and at 1- and 6-month follow-up. RV systolic function was evaluated using five echocardiographic parameters. RV afterload was evaluated using systolic pulmonary arterial pressure and the mean MV pressure gradient. Residual MR was defined as grade ≥ 3 and mitral stenosis (MS) as a mean MV pressure gradient ≥ 5 mm Hg. Sixty-eight patients (52% men; mean age, 75 ± 10 years) were included. Six months after MitraClip implantation, there were no significant changes in any of the RV parameters. MR decreased (P < .01) and the mean MV pressure gradient increased during follow-up (2.3 ± 1.4 mm Hg at baseline vs 4.5 ± 2.7 mm Hg at 6 months, P < .01). Patients with both residual MR and MS 6 months after MitraClip implantation showed significantly higher systolic pulmonary arterial pressure values (P < .01) and lower New York Heart Association functional classes (P < .01) compared with patients without residual MR or MS. Percutaneous MV repair, in contrast to surgical repair or replacement, does not negatively affect RV function. After repair, RV afterload and New York Heart Association functional class are improved in the case of successful repair but adversely affected in the presence of both residual MR and M

A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells

Though Vγ9Vδ2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vγ9Vδ2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vγ9Vδ2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vγ9Vδ2-T cells and EGFR induced potent Vγ9Vδ2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients