The anisotropic Cahn--Hilliard equation: regularity theory and strict separation properties

The Cahn--Hilliard equation with anisotropic energy contributions frequently appears in many physical systems. Systematic analytical results for the case with the relevant logarithmic free energy have been missing so far. We close this gap and show existence, uniqueness, regularity, and separation properties of weak solutions to the anisotropic Cahn--Hilliard equation with logarithmic free energy. Since firstly, the equation becomes highly non-linear, and secondly, the relevant anisotropies are non-smooth, the analysis becomes quite involved. In particular, new regularity results for quasilinear elliptic equations of second order need to be shown.Comment: 39 page

Management of Motion and Anatomical Variations in Charged Particle Therapy:Past, Present, and Into the Future

The major aim of radiation therapy is to provide curative or palliative treatment to cancerous malignancies while minimizing damage to healthy tissues. Charged particle radiotherapy utilizing carbon ions or protons is uniquely suited for this task due to its ability to achieve highly conformal dose distributions around the tumor volume. For these treatment modalities, uncertainties in the localization of patient anatomy due to inter- and intra-fractional motion present a heightened risk of undesired dose delivery. A diverse range of mitigation strategies have been developed and clinically implemented in various disease sites to monitor and correct for patient motion, but much work remains. This review provides an overview of current clinical practices for inter and intra-fractional motion management in charged particle therapy, including motion control, current imaging and motion tracking modalities, as well as treatment planning and delivery techniques. We also cover progress to date on emerging technologies including particle-based radiography imaging, novel treatment delivery methods such as tumor tracking and FLASH, and artificial intelligence and discuss their potential impact towards improving or increasing the challenge of motion mitigation in charged particle therapy

Reduced pain perception in children and adolescents with ADHD is normalized by methylphenidate

Background: The present study examined pain perception in children and adolescents with ADHD and the interaction between pain perception and the administration of methylphenidate (MPH) in order to generate hypotheses for further research that will help to clarify the association between ADHD diagnosis, MPH treatment and pain perception. Methods: We included 260 children and adolescents of the “German Health Interview and Examination Survey for Children and Adolescents” (KiGGS) and analyzed parent’s assessments of children’s pain distribution and pain perception, as well as the influence of MPH administration on pain perception in affected children and adolescents. Results: Pain perception was associated with ADHD and MPH administration, indicating that children and adolescents suffering from ADHD without MPH treatment were reported to have lower pain perception compared to both, healthy controls (HC) and ADHD patients medicated with MPH. Conclusion: We suggest that reduced pain perception in children and adolescents with ADHD not medicated with MPH may lead to higher risk tolerance by misjudgments of dangerous situations, expanding the importance of MPH administration in affected children and adolescents

Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα

Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes.Baden-Württemberg Stiftung; Network of Aging Research (NAR, University of Heidelberg); Deutsche Forschungsgemeinschaft grant: (SFB 1036, TP 12); EMBO Installation Grant number: (2329); Ministry of Education, Youth and Sports of the Czech Republic projects: (LK11206, LO1302); Medical Research Council programme number: (U105178780); Boehringer-Ingelheim

Schreibmotorische Förderung bei Erstklässlern. Ergebnisse einer Interventionsstudie

Die vorliegende Interventionsstudie wurde im Schuljahr 2014/2015 bei 102 Erstklässlern durchgeführt [...]. Es wurde untersucht, ob ein spezielles schreibmotorisch orientiertes Übungsprogramm zu einer zügigeren Entwicklung der motorischen Schreibkompetenzen der Kinder einer Interventionsgruppe führt [...]. Es zeigte sich, dass sich die motorischen Kompetenzen der Kinder in der Interventionsgruppe im Verlauf des Schuljahrs im Vergleich zu der Kontrollgruppe besser entwickelten: Zum Ende des Schuljahres schrieben sie das gleiche Testwort signifikant schneller als die Kinder in der Kontrollgruppe. Zugleich schrieben sie das Testwort mit Schlaufen mit einem signifikant geringeren Schreibdruck als die Kinder in der Kontrollgruppe. Beides ist auch als ein erster Schritt hin zu einer früheren Bewegungsautomatisierung zu werten. (DIPF/Orig.)This intervention study was carried out in the 2014/2015 school year among 102 first-year pupils (six classes from four mainstream schools). The study analysed whether a special writing motor-oriented exercise programme would lead to a more rapid development of writing motor skills in children in an intervention group when compared to the expected development of a control group that only went through regular writing lessons. Writing movements were recorded with the help of a graphics tablet and analysed according to kinematic aspects (writing frequency and writing pressure). It was clear that, over the course of the school year, the writing motor skills of the children in the intervention group became better developed than those in the control group: the children wrote the same testword significantly faster at the end of the school year than the children in the control group.At the same time, they applied significantly less pressure when writing the test word and loops than the children in the control group.Both of these things can be seen as a first step towards early automation ofmovements. (DIPF/Orig.

Digitale Workshops in der Lehrkräftebildung. Chancen und Grenzen der Interaktion im digitalen Raum

Die Autor*innen erörtern Chancen und Herausforderungen der Interaktion im digitalen Raum, exemplifiziert an der digitalen Workshopreihe „Sprachliche Vielfalt mit digitalen Medien fördern, nutzen und gestalten“ (Lehr-Lern-Atelier des Instituts für Sprachen und Mehrsprachigkeit). Die Workshopreihe adressiert den Umgang mit sprachlicher, kultureller und ethnischer Heterogenität und zielt gleichzeitig auf eine Förderung digitalisierungsbezogener Kompetenzen von Lehrkräften ab. Die Autor*innen zeigen auf, wie Selbstlern- und kollaborative Arbeitsphasen sowie innovative Austauschformate – vor dem Hintergrund der Pandemiebedingungen – eine Interaktion zwischen den Teilnehmenden (auch) im digitalen Raum initiieren können. (DIPF/Orig.

Expression of Kallikrein-related peptidase 6 in primary mucosal malignant melanoma of the head and neck

Mucosal melanomas of the head and neck (MMHN) are aggressive tumors with poor prognosis, different opposed to cutaneous melanoma. In this study, we characterized primary mucosal malignant melanoma for the expression of Kallikrein-related peptidase 6 (KLK6), a member of the KLK family with relevance to the malignant phenotype in various cancer types including cutaneous melanoma. Paraffin-embedded MMHN of 22 patients were stained immunohistochemically for KLK6 and results were correlated with clinical and pathological data. In 77.3% (17/22) of MMHN cases, positive KLK6 staining was found. Staining pattern for tumor cells showed a predominant cytoplasmic staining. However, in six cases we also observed a prominent nuclear staining. MMHN with a high KLK6 expression showed significantly better outcome concerning local recurrence-free survival (p = 0.013) and nuclear KLK6 staining was significantly associated with the survival status (p = 0.027). Overexpression of KLK6 was detected in more than 70% of MMHN and approximately 40% of tumors showed a strong expression pattern. Correlation between clinical outcome of MMHN patients and overexpression of KLK6 has not been addressed so far. Our data demonstrate for the first time increased levels of KLK6 in MMHN and strengthen the hypothesis that there might be a context-specific regulation and function of KLK6 in mucosal melanoma

Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation

The immediate tissue microenvironment of implanted biomedical devices and engineered tissues is highly influential on their long term fate and efficacy. The creation of a long-term anti-inflammatory microenvironment around implants and artificial tissues can facilitate their integration. Macrophages are highly plastic cells that define the tissue reactions on the implanted material. Local control of macrophage phenotype by long-term fixation of their healing activities and suppression of inflammatory reactions are required to improve implant acceptance. Herein, we describe the development of a cytokine cocktail (M2Ct) that induces stable M2-like macrophage phenotype with significantly decreased pro-inflammatory cytokine and increased anti-inflammatory cytokine secretion profile. The positive effect of the M2Ct was shown in an in vitro wound healing model; where M2Ct facilitated wound closure by human fibroblasts in co-culture conditions. Using a model for induction of inflammation by LPS we have shown that the M2Ct phenotype is stable for 12 days. However, in the absence of M2Ct in the medium macrophages underwent rapid pro-inflammatory re-programming upon IFNg stimulation. Therefore, loading and release of the cytokine cocktail from a self-standing, transferable gelatin/tyraminated hyaluronic acid based release system was developed to stabilize macrophage phenotype for in vivo applications in implantation and tissue engineering. The M2Ct cytokine cocktail retained its anti-inflammatory activity in controlled release conditions. Our data indicate that the direct application of a potent M2 inducing cytokine cocktail in a transferable release system can significantly improve the long term functionality of biomedical devices by decreasing pro-inflammatory cytokine secretion and increasing the rate of wound healing