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Abstract Autoimmune diseases result from autoantigen-mediated activation of adaptive immunity; intriguingly, autoantigen-specific T cells are also present in healthy donors. An assessment of dynamic changes of this autoreactive repertoire in both health and disease is thus warranted. Here we investigate the physiological versus pathogenic autoreactive processes in the context of Type 1 diabetes (T1D) and one of its landmark autoantigens, glutamic acid decarboxylase 65 (GAD65). Using single cell gene expression profiling and tandem T cell receptor (TCR) sequencing, we find that GAD65-specific true naïve cells are present in both health and disease, with GAD65-specific effector and memory responses showing similar ratios in healthy donors and patients. Deeper assessment of phenotype and TCR repertoire uncover differential features in GAD65-specific TCRs, including lower clonal sizes of healthy donor-derived clonotypes in patients. We thus propose a model whereby physiological autoimmunity against GAD65 is needed during early life, and that alterations of these physiological autoimmune processes in predisposed individuals trigger overt Type 1 diabetes.

Advancements in personalized medicine, threedimensional (3D) printing, miniaturization, and robot-assisted surgery are driving innovation in tissue engineering. A novel approach, known as in situ printing, focuses on the direct deposition of materials at the surgical site. Using the in situ printing approach, bone and/or cartilage defects can be addressed with high precision. Furthermore, highly customized 3D printed tissue constructs or implants can be deposited directly inside the body. Currently, most applications of in situ printing are limited to areas near the skin or open surgeries. Even though a minimally invasive approach would bring clinical benefits, only a few research groups have focused on this field. In this scoping review, we provide an overview of the current state of in situ minimally invasive 3D printing technology for bone and cartilage regeneration and discuss its advantages and current challenges.

Neuropeptide Y (NPY) and related peptides have been proposed as promising biomarkers for the diagnosis of prostate cancer by previous immunoassays and immunohistochemical studies. In this study, we evaluated the additional value of NPY and related peptides compared with prostate-specific antigen (PSA). We performed a comprehensive analysis of NPY, its precursors, and metabolite concentrations in both plasma and tissue samples from 181 patients using a highly specific liquid chromatography tandem mass spectrometry method. Compared with PSA, NPY and related peptides (NPYs) were less accurate at diagnosing significant prostate cancer. Combinations of NPYs in a stepwise approach did not improve a model that would be beneficial for patients. NPY may be beneficial for patients presenting with a PSA concentration in the gray area between 4 and 9 ng/ml, but the strength of this conclusion is limited. Thus, the use of NPYs as standalone or in combination with other variables, such as PSA, prostate volume, or age, to improve the diagnosis is not supported by our study. Patient summary: This study evaluated neuropeptide Y (NPY) of the family of endogenous peptides as a new biomarker to diagnose prostate cancer. We found that NPY in a patient’s blood was not more helpful at diagnosing prostate cancer than the standard prostate-specific antigen blood test. Further research is needed to explore the potential of NPY and related peptides in specific subgroups of patients.

Mostly aimed at an audience with backgrounds in geometry and homological algebra, these notes offer an introduction to derived geometry based on a lecture course given by the second author. The focus is on derived algebraic geometry, mainly in characteristic 0, but we also see the tweaks which extend most of the content to analytic and differential settings

Small group learning activities have been shown to improve student academic performance and educational outcomes. Yet, we have an imperfect understanding of the mechanisms by which this occurs. Group learning may mediate student stress by placing learning in a context where students have both social support and greater control over their learning. We hypothesize that one of the methods by which small group activities improve learning is by mitigating student stress. To test this, we collected physiological measures of stress and self-reported perceived stress from 26 students in two undergraduate classes. Salivary cortisol and testosterone were measured within students across five contexts: a) pre-instructional baseline, b) following a traditional lecture, c) after participating in a structured small group learning activity, d) following completion of multiple choice, and e) essay sections of an exam. Results indicate students have lower salivary cortisol after small group learning activities, as compared to traditional lectures. Further, there is no evidence of a relationship between physiological measures of stress and self-reported perceived stress levels. We discuss how structured small group activities may be beneficial for reducing stress and improving student-learning outcomes.

Abstract Background Neuroblastoma (NB) and pheochromocytoma/paraganglioma (PHEO/PGL) are neuroendocrine tumors. Imaging of these neoplasms is performed by scintigraphy after injection of radiolabeled meta-iodobenzylguanidine (mIBG), a norepinephrine analog taken up by tumoral cells through monoamine transporters. The pharmacological induction of these transporters is a promising approach to improve the imaging and therapy (theranostics) of these tumors. Methods Transporters involved in mIBG internalization were identified by using transfected Human Embryonic Kidney (HEK) cells. Histone deacetylase inhibitors (HDACi) and inhibitors of the PI3K/AKT/mTOR pathway were tested in cell lines to study their effect on mIBG internalization. Studies in xenografted mice were performed to assess the effect of the most promising HDACi on 123I-mIBG uptake. Results Transfected HEK cells demonstrated that the norepinephrine and dopamine transporter (NET and DAT) avidly internalizes mIBG. Sodium-4-phenylbutyrate (an HDACi), CUDC-907 (a dual HDACi and PI3K inhibitor), BGT226 (a PI3K inhibitor) and VS-5584 and rapamycin (two inhibitors of mTOR) increased mIBG internalization in a neuroblastoma cell line (IGR-NB8) by 2.9-, 2.1-, 2.5-, 1.5- and 1.3-fold, respectively, compared with untreated cells. CUDC-907 also increased mIBG internalization in two other NB cell lines and in one PHEO cell line. We demonstrated that mIBG internalization occurs primarily through the NET. In xenografted mice with IGR-NB8 cells, oral treatment with 5 mg/kg of CUDC-907 increased the tumor uptake of 123I-mIBG by 2.3- and 1.9-fold at 4 and 24 h post-injection, respectively, compared to the untreated group. Conclusions Upregulation of the NET by CUDC-907 lead to a better internalization of mIBG in vitro and in vivo.

Gonadotropin-releasing hormone agonists (GnRHa's) are the standard treatment for children with central precocious puberty (CPP). We aim to present data on available GnRHa options with an easy-to-review table and discuss factors that influence treatment selection. Five GnRHa's are currently FDA-approved and prescribed in the US and published data suggest similar safety and efficacy profiles over the first year of treatment. One- and 3-month intramuscular (IM) leuprolide acetate (LA) have long-term safety and efficacy data and allow for flexible dosing. Six-month IM triptorelin pamoate offers a longer duration of treatment, but without long-term efficacy and outcome data. Six-month subcutaneous (SQ) LA combines a SQ route of injection and long duration of action but lacks long-term efficacy and outcome data. The 12-month SQ histrelin acetate implant avoids injections and offers the longest duration of action, but requires a minor surgical procedure with local or general anesthesia. Factors in treatment selection include route of administration, needle size, injection volume, duration of action, and cost. The current GnRHa landscape provides options with varying benefits and risks, allowing physicians and caregivers to select the most appropriate therapy based on the specific needs and concerns of the child and the caregiver. Agents have different advantages and disadvantages for use, with no one agent displaying superiority.

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Der Beitrag stellt das Projekt Kreativmarkt @Smartfeld und dessen Effekte bezüglich Selbstvertrauen, Selbstständigkeit, Selbstwirksamkeit und Durchhaltewillen von Kindern aus der 5. und 6. Primarschulklasse vor, welche im Rahmen eines Pilots untersucht wurden. Beim Kreativmarkt handelt es sich um ein interdisziplinäres Projekt zur Förderung von Zukunftskompetenzen und Entrepreneurship des Bildungslabors Smartfeld in St. Gallen, Schweiz. Für den Kreativmarkt @Smartfeld entwickelten Kinder in ihrer Freizeit ein Produkt oder ein Dienstleistungsangebot, welches sie während der publikumsoffenen Veranstaltung an die Öffentlichkeit verkauften. Dazu besuchten sie fünf Workshops mit verschiedenen Themenschwerpunkten wie Design Thinking, Entrepreneurship, finanzielle Bildung und Upcycling. Begleitend zum Projekt wurde in einer Studie (n = 36) untersucht, inwiefern sich die Teilnahme auf das Selbstvertrauen, die Selbstständigkeit, die Selbstwirksamkeit und das Durchhaltevermögen auswirkt. Beim Selbstvertrauen und der Selbstständigkeit wurden positive Effekte festgestellt, bei der Selbstwirksamkeit und dem Durchhaltevermögen waren die Effekte negativ. Die Ergebnisse aus der quantitativen Befragung waren nicht signifikant. Ergänzend wurden mit einigen Kindern (n = 5) Interviews durchgeführt. Diese haben ergeben, dass die Schüler:innen es schätzten beim Projekt eigenständig ein Produkt entwickeln und so ihre eigenen Ideen in die Tat umzusetzen zu können. Weiter haben sie auf verschiedenen Ebenen dazugelernt, wie beispielsweise bei der Produktion oder der Preisgestaltung. Auch die kollaborative Arbeitsweise empfanden die Kinder als wichtig und bereichernd. Nicht zuletzt hat ihnen die Teilnahme Spass gemacht und die Freude über den eigens erwirtschafteten Gewinn war gross.

The following authors were omitted from the original version of this Data Descriptor: Markus Reichstein and Nicolas Vuichard. Both contributed to the code development and N. Vuichard contributed to the processing of the ERA-Interim data downscaling. Furthermore, the contribution of the co-author Frank Tiedemann was re-evaluated relative to the colleague Corinna Rebmann, both working at the same sites, and based on this re-evaluation a substitution in the co-author list is implemented (with Rebmann replacing Tiedemann). Finally, two affiliations were listed incorrectly and are corrected here (entries 190 and 193). The author list and affiliations have been amended to address these omissions in both the HTML and PDF versions.

University teachers work in a highly complex environment, meeting the multiple and sometimes competing demands of striving for high quality teaching and research. While a growing body of research focuses on the relevance of schoolteachers' sense of responsibility and its outcomes for teaching and student learning, teacher responsibility has been neglected in research with university teachers. This research, consisting of two consecutive qualitative and quantitative studies, sets out to explore university teachers' sense of responsibility for teaching at different stages of their career and in different academic contexts. Participants were 199 German and 80 Australian university teachers. Results of quantitative data analysis show that all university teachers most strongly feel responsible for their teaching and relationships with students. The focus of university teachers' sense of responsibility on teaching was also shown in the qualitative data. Differences between the samples of the two studies, however, appeared with regard to further objects of responsibility. Cluster analyses, including the frequencies of statements, revealed three types of university teachers in each study: teaching- and student-oriented university teachers in both studies, achievement-oriented teachers in the German/Swiss, and administrative-oriented university teachers in the Australian sample. Implications for university teachers' work contexts and training are discussed.