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The developmental stages (larva, pupa) of Anthonomus brunnipennis are fully described for the first time. Despite great similarities of the adults of A. brunnipennis and A. rubi the differences between immature stages of both species could be demonstrated. Two different habitats of A. brunnipennis in Germany are described, and host plant data are critically reviewed. The only well-documented host plant of A. brunnipennis is Potentilla erecta.

Abstract Background Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA’s full potential, this study introduces a novel approach for CTC enrichment from DLAs. Methods DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations. Results Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes. Conclusions In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.

Abstract Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab‐paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab‐paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab‐paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab‐paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT‐Nr. 2019‐001439‐29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab‐paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large‐scale clinical study.

Abstract Chronic kidney disease (CKD) is characterized by an elevated risk for cerebrovascular disease including stroke. One mechanism that may contribute to this heightened risk is an impairment in cerebrovascular carbon dioxide reactivity (CVR). We compared CVR between CKD patients stages III–IV and controls (CON) without CKD but matched for hypertension and diabetes status. CVR was measured via 5% CO2 inhalation followed by voluntary hyperventilation in 14 CKD and 11 CON participants while mean arterial pressure, end‐tidal carbon dioxide, and middle cerebral artery blood velocity (MCAv) were measured continuously. CVR was quantified as the linear relationship between etCO2 and MCAv. We observed no difference in CVR between groups. Hypercapnic CVR: CKD = 1.2 ± 0.9 cm/s/mm Hg, CON = 1.3 ± 0.8 cm/s/mm Hg, hypocapnic CVR: CKD = 1.3 ± 0.9 cm/s/mm Hg, CON = 1.5 ± 0.7 cm/s/mm Hg, integrated CVR: CKD = 1.5 ± 1.1 cm/s/mm Hg, CON = 1.7 ± 0.8 cm/s/mm Hg, p ≥ 0.48. Unexpectedly, CVR was inversely related to estimated glomerular filtration rate in CKD (R2 = 0.37, p = 0.02). We report that CVR remains intact in CKD and is inversely related to eGFR. These findings suggest that other mechanisms beyond CVR contribute to the elevated stroke risk observed in CKD.

Mit Blick auf eine zu erwartende Ausweitung von Programmen künstlerischer Musikforschung an deutschen Musikhochschulen befasst sich der Artikel mit einer kritischen Re-Lektüre der Empfehlungen zur postgradualen Qualifikationsphase an Kunst- und Musikhochschulen des Wissenschaftsrates (2021), die mit Aspekten aus Thomas S. Kuhns Buch Die Struktur wissenschaftlicher Revolutionen enggeführt wird. Auf dieser Grundlage wird zu einer mehr oder weniger spekulativ gehaltenen Skizze von Zukunftsszenarien einer musiktheoretisch inspirierten künstlerischen Musikforschung angesetzt. With a view to the expected expansion of artistic music research programs at German music universities, the article deals with a critical re-reading of the recommendations on the postgraduate qualification phase at art and music universities of the German Council of Science and Humanities (2021), which is closely linked to aspects of Thomas S. Kuhn’s book The Structure of Scientific Revolutions. On this basis, a more or less speculative sketch of future scenarios for artistic music research inspired by music theory is presented.

This manuscript describes a major revision and update of the First Step to Success Early Intervention Program, now called First Step Next. The original First Step Program was published in 1997 and the revised, updated version was published in 2015 (Walker et al.). First Step Next is a collaborative, Tier II school- and family-supported early intervention that teaches school success skills to give students the best start possible in their school career. This manuscript covers five major topics: (1) program history, (2) rationale and procedures for the First Step revision, (3) First Step Next implementation, (4) maintenance and follow up procedures, and (5) current and future research on First Step Next.

The mature larva of the weevil species Orobitis cyanea (Linnaeus, 1758), one of only two Palaearctic members of the supertribe Orobitiditae, is re-described, while the pupa is described for the first time. The biology of this species was studied at two sites in Germany. It was reared from seed capsules of Viola canina L. (Violaceae), and feeding holes were observed on V. riviniana Rchb. Adults of Orobitis cyanea and O. nigrina Reitter, 1885, specialists of Viola, show a well-developed escape mechanism, to which contribute a smooth surface, a rounded, nearly spherical body shape, and a seed-imitating thanatosis behaviour. The molytine weevil Leiosoma cribrum (Gyllenhal, 1834), the only other known weevil specialist of Viola in Europe, has a smooth surface, also, and is the most spherical species of the genus. The unique characters of the larva and pupa of Orobitis cyanea are discussed in regard to the systematic position of this taxon.

BACKGROUND Chronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS), which increases the risk of cardiovascular (CV) disease and mortality. SNS overactivity increases CV risk by multiple mechanisms, including vascular stiffness. We tested the hypothesis that aerobic exercise training would reduce resting SNS activity and vascular stiffness in patients with CKD.METHODS In this randomized controlled trial, sedentary older adults with CKD underwent 12 weeks of exercise (cycling, n = 32) or stretching (an active control group, n = 26). Exercise and stretching interventions were performed 20–45 minutes/session at 3 days/week and were matched for duration. Primary endpoints include resting muscle sympathetic nerve activity (MSNA) via microneurography, arterial stiffness by central pulse wave velocity (PWV), and aortic wave reflection by augmentation index (AIx).RESULTS There was a significant group × time interaction in MSNA and AIx with no change in the exercise group but with an increase in the stretching group after 12 weeks. The magnitude of change in MSNA was inversely associated with baseline MSNA in the exercise group. There was no change in PWV in either group over the study period.CONCLUSION Our data demonstrate that 12 weeks of cycling exercise has beneficial neurovascular effects in patients with CKD. Specifically, exercise training safely and effectively ameliorated the increase in MSNA and AIx observed over time in the control group. This sympathoinhibitory effect of exercise training showed greater magnitude in patients with CKD with higher resting MSNA.TRIAL REGISTRATION ClinicalTrials.gov, NCT02947750.FUNDING NIH R01HL135183; NIH R61AT10457; NIH NCATS KL2TR002381; and NIH T32 DK00756; NIH F32HL147547; and VA Merit I01CX001065.

Ella H Leung,1 Sahana Sharma,2 Ana Levie-Sprick,1 Gregory D Lee,1 Hyung Cho,1 Krishna Mukkamala1 1Georgia Retina, Atlanta, GA, USA; 2Vanderbilt University, Nashville, TN, USACorrespondence: Ella H LeungGeorgia Retina, 833 Campbell Hill St NW, Suite 300, Marietta, GA, 30060, USATel +1-770-218-1888Email eleung@garetina.comPurpose: To evaluate the risk factors and fundus findings of patients with potential PPS-associated retinopathy.Patients and Methods: A retrospective chart review was performed of patients exposed to PPS who had a dilated fundus examination at a large retina-only practice from 2018– 21. Multimodal images were evaluated by masked reviewers.Results: A total of 148 patients were included, of whom 33 (22%) had PPS-associated retinopathy, and 115 (78%) did not. The mean age was 60.3 years old, and the mean follow-up was 11.8 months. The PPS-associated retinopathy group had higher mean cumulative doses of PPS (1600g± 849 vs 864g± 852, P < 0.0001, Mann–Whitney test) and longer duration of PPS use (13.6 years vs 7.48, P < 0.0001). There was no statistically significant difference based on a history of kidney or liver disease or the dosage per day for the weight, body mass index, body surface area, or lean body weight. Of the patients with PPS-associated retinopathy whose genetic results were available, 15 of 16 (93%) were heterozygous for variants of uncertain significance.Conclusion: A longer duration of PPS use and higher cumulative dosage of PPS were associated with an increased risk of developing PPS-associated pigmentary retinopathy. The role of genetic mutations in patients exposed to PPS is still to be determined.Keywords: pentosan polysulfate sodium, pigmentary retinopathy, pharmacotoxicity, inherited retinal dystrophies, genetics

Abstract Chronic Kidney Disease (CKD) patients experience an elevated risk for cerebrovascular disease. One factor that may contribute to this heightened risk is an impairment in dynamic cerebral autoregulation, the mechanism by which cerebral vessels modulate cerebral blood flow during fluctuations in arterial pressure. We hypothesized that dynamic cerebral autoregulation would be impaired in CKD. To test this hypothesis, we compared dynamic cerebral autoregulation between CKD patients stages III‐IV and matched controls (CON) without CKD. Fifteen patients with CKD and 20 CON participants performed 2, 5‐minute bouts of repeated sit‐to‐stand maneuvers at 0.05 Hz and 0.10 Hz while mean arterial pressure (MAP, via finger photoplethysmography) and middle cerebral artery blood velocity (MCAv, via transcranial Doppler ultrasound) were measured continuously. Cerebral autoregulation was characterized by performing a transfer function analysis (TFA) on the MAP‐MCAv relationship to derive coherence, phase, gain, and normalized gain (nGain). We observed no group differences in any of the TFA metrics during the repeated sit‐to‐stand maneuvers. During the 0.05 Hz maneuver, Coherence: CKD = 0.83 ± 0.13, CON = 0.85 ± 0.12, Phase (radians): CKD = 1.39 ± 0.41, CON = 1.25 ± 0.30, Gain (cm/s/mmHg): CKD = 0.69 ± 0.20, CON = 0.71 ± 0.22, nGain (%/mmHg): CKD = 1.26 ± 0.35, CON = 1.20 ± 0.28, p ≥ 0.24. During the 0.10 Hz maneuver (N = 6 CKD and N = 12 CON), Coherence: CKD = 0.61 ± 0.10, CON = 0.67 ± 0.11, Phase (radians): CKD = 1.43 ± 0.26, CON = 1.30 ± 0.23, Gain (cm/s/mmHg): CKD = 0.75 ± 0.15, CON = 0.84 ± 0.26, nGain (%/mmHg): CKD = 1.50 ± 0.28, CON = 1.29 ± 0.24, p ≥ 0.12. Contrary to our hypothesis, dynamic cerebral autoregulation remains intact in CKD stages III‐IV. These findings suggest that other mechanisms likely contribute to the increased cerebrovascular disease burden experienced by this population. Future work should determine if other cerebrovascular regulatory mechanisms are impaired and related to cerebrovascular disease risk in CKD.

The extreme oxygen sensitive character of hydrogenases is a longstanding issue for hydrogen production in bacteria. Here, the authors build carboxysome shells in E. coli and incorporate catalytically active hydrogenases and functional partners within the empty shell for the production of hydrogen.

We describe herein non-integrating minimally sized nano-S/MAR DNA vectors, which can be used to genetically modify dividing cells in place of integrating vectors. They represent a unique genetic tool, which avoids vector-mediated damage. Previous work has shown that DNA vectors comprising a mammalian S/MAR element can provide persistent mitotic stability over hundreds of cell divisions, resisting epigenetic silencing and thereby allowing sustained transgene expression. The composition of the original S/MAR vectors does present some inherent limitations that can provoke cellular toxicity. Herein, we present a new system, the nano-S/MAR, which drives higher transgene expression and has improved efficiency of establishment, due to the minimal impact on cellular processes and perturbation of the endogenous transcriptome. We show that these features enable the hitherto challenging genetic modification of patient-derived cells to stably restore the tumor suppressor gene SMAD4 to a patient-derived SMAD4 knockout pancreatic cancer line. Nano-S/MAR modification does not alter the molecular or phenotypic integrity of the patient-derived cells in cell culture and xenograft mouse models. In conclusion, we show that these DNA vectors can be used to persistently modify a range of cells, providing sustained transgene expression while avoiding the risks of insertional mutagenesis and other vector-mediated toxicity.

The mature larva and pupa of Otiorhynchus smreczynskii are described and illustrated with complete chaetotaxy for the first time. Five larval instars and the factors for larval growth are determined, and the larval development of this species is comprehensively described. In order to confirm species affiliation, selected larvae were subjected to genetic analysis (mtCOI). Host plants and unique feeding signs of some Entiminae species are presented, and all available data on development are documented and interpreted. Additionally, the morphometry of 78 specimens (48 of O. smreczynskii and 30 of O. rotundus) was examined in order to verify the usefulness of morphological features in distinguishing both species. The female genitalia of both species are illustrated, described and compared with each other for the first time. Finally, the updated distribution of O. smreczynskii is given, and a possible origin of O. smreczynskii and O. rotundus is proposed.

Background: Chronic kidney disease (CKD) patients have exercise intolerance and exaggerated blood pressure reactivity during exercise that are mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. Activation of the renin-angiotensin system (RAS) increases SNS activation and reduces NO synthesis, and prior studies suggest that RAS blockade attenuates declines in physical function. We hypothesized that RAS inhibitor (RASi) use is associated with higher exercise capacity mediated by decreased SNS activity and increased NO-dependent endothelial function in CKD. Method: In 35 CKD patients (57 ± 7 years) and 20 controls (CON, 53 ± 8 years), we measured exercise capacity (VO2peak), muscle sympathetic nervous activity (MSNA) and flow-mediated dilation (FMD) for NO-dependent endothelial function. Results: CKD patients treated with RASi (CKD+RASi, n=25) had greater VO2 peak compared to CKD patients not treated with RASi (CKD no RASi, n=10), but lower VO2 peak compared to CON (23.3 ± 5.8 vs.16.4 ± 2.9, p=0.007; vs.30.0 ± 7.7, p=0.016 ml/min/kg respectively). CKD+RASi had lower resting MSNA and greater FMD compared to CKD no RASi. Compared to CON, CKD+RASi had similar MSNA but lower FMD. VO2 peak was positively associated with FMD (r=0.417, p=0.038) and was predicted by the combination of FMD and RASi status (r2 =0.344, p=0.01) and MSNA and RASi status (r2 =0.575, p=0.040) in CKD patients. Conclusion: In summary, CKD patients on RASi have higher exercise capacity compared to those not on RASi. Higher exercise capacity in RASi-treated group was associated with lower resting SNS activity and higher NO-dependent vascular endothelial function.

The direct conversion of sunlight into hydrogen through water splitting, and by converting carbon dioxide into useful chemical building blocks and fuels, has been an active area of research since early reports in the 1970s. Most of the semiconductors that drive these photocatalytic processes have been inorganic semiconductors, but since the first report of carbon nitride organic semiconductors have also been considered. Conjugated materials have been relatively extensively studied as photocatalysts for solar fuels generation over the last 5 years due to the synthetic control over composition and properties. The understanding of materials’ properties, its impact on performance and underlying factors is still in its infancy. Here, we focus on the impact of interfaces, and nanostructure on fundamental processes which significantly contribute to performance in these organic photocatalysts. In particular, we focus on presenting explicit examples in understanding the interface of polymer photocatalysts with water and how it affects performance. Wetting has been shown to be a clear factor and we present strategies for increased wettability in conjugated polymer photocatalysts through modifications of the material. Furthermore, the limited exciton diffusion length in organic polymers has also been identified to affect the performance of these materials. Addressing this, we also discuss how increased internal and external surface areas increase the activity of organic polymer photocatalysts for hydrogen production from water.

The mature larva of Sciaphilus asperatus is redescribed and illustrated, and the pupa is described for the first time. Supplements to the identification keys for larvae and pupae of selected Palaearctic Entiminae genera and species are given. Data on the life history, especially oviposition capacity and voltinism, of S. asperatus are provided and discussed, and the number of the six larval instars was confirmed. The economic importance of S. asperatus is briefly highlighted.

Objective: To assess the inter-evaluator and intra-evaluator reliability of a software program used to extract kinematic variables by a commercially available extremity-mounted inertial measurement unit system in sound horses at the trot under soft and hard ground conditions and treadmill exercise.Animals: Thirty adult, sound and healthy French Montagne stallions.Procedures: Data collection was performed with six IMUs strapped to the distal, metacarpal, metatarsal and tibial regions of every horse. Per surface (treadmill, soft and hard ground) 10 stallions were trotted three times. Prior to the analysis done by six evaluators (three experienced, three inexperienced) the data was blinded and copied three times. For every analysis a minimum of five strides had to be selected. To assess the intra- and inter-evaluator reliability a selection of gait variables was used to calculate intra and inter correlation coefficients (ICCs) as well as variance partitioning coefficients (VPCs).Results: All of the tested gait variables showed high levels of reliability. There was no mentionable difference considering the correlation coefficients between the intra and inter reliability as well as between the three different surfaces. VPCs showed that the factor horse is by far the most responsible for any appearing variance. The experience of the evaluator had no influence on the results.Conclusions and Clinical Relevance: The software program tested in this study has a high inter- and intra-evaluator reliability under the chosen conditions for the selected variables and acts independent of the ground situation and the experience of the evaluator. On the condition of a correct application it has the potential to become a clinically relevant and reliable gait analysis tool.

Cerebrovascular control and its integration with other physiological systems play a key role in the effective maintenance of homeostasis in brain functioning. Maintenance, restoration, and promotion of such a balance are one of the paramount goals of brain rehabilitation and intervention programs. Cerebrovascular reactivity (CVR), an index of cerebrovascular reserve, plays an important role in chemo-regulation of cerebral blood flow. Improved vascular reactivity and cerebral blood flow are important factors in brain rehabilitation to facilitate desired cognitive and functional outcomes. It is widely accepted that CVR is impaired in aging, hypertension, and cerebrovascular diseases and possibly in neurodegenerative syndromes. However, a multitude of physiological factors influence CVR, and thus a comprehensive understanding of underlying mechanisms are needed. We are currently underinformed on which rehabilitation method will improve CVR, and how this information can inform on a patient’s prognosis and diagnosis. Implementation of targeted rehabilitation regimes would be the first step to elucidate whether such regimes can modulate CVR and in the process may assist in improving our understanding for the underlying vascular pathophysiology. As such, the high spatial resolution along with whole brain coverage offered by MRI has opened the door to exciting recent developments in CVR MRI. Yet, several challenges currently preclude its potential as an effective diagnostic and prognostic tool in treatment planning and guidance. Understanding these knowledge gaps will ultimately facilitate a deeper understanding for cerebrovascular physiology and its role in brain function and rehabilitation. Based on the lessons learned from our group’s past and ongoing neurorehabilitation studies, we present a systematic review of physiological mechanisms that lead to impaired CVR in aging and disease, and how CVR imaging and its further development in the context of brain rehabilitation can add value to the clinical settings.

Accidental exposure to ionizing radiation may lead to delayed effects of acute radiation exposure (DEARE) in many organ systems. Activated protein C (APC) is a known mitigator of the acute radiation syndrome. To examine the role of APC in DEARE, we used a transgenic mouse model with 2- to 3-fold increased plasma levels of APC (high in APC, APCHi). Male and female APCHi mice and wild-type littermates were exposed to 9.5 Gy γ-rays with their hind-legs (bone marrow) shielded from radiation to allow long-term survival. At 3 and 6 months after irradiation, cardiac function was measured with ultrasonography. At 3 months, radiation increased cardiac dimensions in APCHi males, while decreases were seen in wild-type females. At this early time point, APCHi mice of both sexes were more susceptible to radiation-induced changes in systolic function compared to wild-types. At 6 months, a decrease in systolic function was mainly seen in male mice of both genotypes. At 6 months, specimens of heart, small intestine and dorsal skin were collected for tissue analysis. Female APCHi mice showed the most severe radiation-induced deposition of cardiac collagens but were protected against a radiation-induced loss of microvascular density. Both male and female APCHi mice were protected against a radiation induced upregulation of toll-like receptor 4 in the heart, but this did not translate into a clear protection against immune cell infiltration. In the small intestine, the APCHi genotype had no effect on an increase in the number of myeloperoxidase positive cells (seen mostly in females) or an increase in the expression of T-cell marker CD2 (males). Lastly, both male and female APCHi mice were protected against radiation-induced epidermal thickening and increase in 3-nitrotyrosine positive keratinocytes. In conclusion, prolonged high levels of APC in a transgenic mouse model had little effects on indicators of DEARE in the heart, small intestine and skin, with some differential effects in male compared to female mice.

China’s public security forces are employing more and more technology in their push for an ‘informatization (信息化)’ of their police work. The application of analytical techniques for solving past crimes or preventing future crimes based on big data analysis is thereby a key component of China’s approach for technology-led policing. China’s holistic policy approach for the purpose of maintaining social stability that is encompassing an ever-growing range of societal issues, the vast investments of its police forces in new technologies and its paramount objective of security, that clearly supersedes inter alia concerns of privacy or transparency, may be considered extremely conducive to the establishment of effective predictive policing in China. This paper however argues, that the application of predictive policing in China is heavily flawed as the systemic risks and pitfalls of predictive policing cannot be mitigated but are rather exacerbated by China’s approach towards policing and its criminal justice system. It is therefore to be expected that predictive policing in China will mainly be a more refined tool for the selective suppression of already targeted groups by the police and does not substantially reduce crime or increase overall security.

The mature larva and pupa of Graptus triguttatus triguttatus and the mature larva of Peritelus sphaeroides are described for the first time. The larvae of Philopedon plagiatum and Tanymecus palliatus are re-described. Five larval instars were determined in Tanymecus, thereby correcting doubtful data in the literature. The relationship between larval growth, number of larval instars, head width of the mature larva, and the adult weevil is explained using the example of Tanymecus. The nearly constant ratio of subsequent larval instars in head width ratio, termed “growth factor” and derived from Dyar’s ratio, is used for the determination of larval instars. Larval collecting and breeding data are discussed in relation to their significance for the clarification of life-cycles.

While inorganic semiconductors are well-studied for their solar-to-fuel energy conversion abilities, organic materials receive far less attention. Here, authors prepare linear conjugated polymers as H2 evolution photocatalysts and rationalize photocatalytic activities with fundamental properties.

Polarisation of metastasising cancer cells in circulation has not been investigated before. Here the authors identify single cell polarity as a distinct polarisation state of single cells in liquid phase, and show that perturbing single cell polarity affects attachment, adhesion, transmigration and metastasis in vitro and in vivo.

Abstract Ovarian cancer has the worst prognosis of all gynecological cancers with high‐grade serous ovarian cancer (HGSOC) accounting for the majority of ovarian cancer deaths. Therapy resistance and the selection of effective therapies for patients remains a major challenge. In this issue of EMBO Molecular Medicine, Hoppe et al present RAD51 expression as a biomarker of platinum resistance in high‐grade serous ovarian cancer (HGSOC) patients (Hoppe et al, 2021).

An increasing number of patients with prolonged waiting times or difficulties to get admittance to the health system has enforced the number of internet-based psychotherapy treatments in many countries. There is a wide range of solutions ranging from self-help to guided or therapist-delivered versions. Advantages and disadvantages of the different treatment approaches will be highlighted. Completer rates and effects of different e-health treatments will be compared with face to face treatments. Additionally different quality parameters of internet-based psychotherapy will be focused.

Abstract Cancer drug screening in patient‐derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced, matrix‐dependent organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy‐based assay to resolve drug‐induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevant drugs. Drug‐induced growth arrest and efficacy of cytostatic drugs differed between the two culture systems. Interestingly, drug effects in organoids were more diverse and had lower therapeutic potential. Genomic analysis revealed novel links between drug sensitivity and DNA repair deficiency in organoids that were undetectable in monolayers. Thus, our results highlight the dependency of cytostatic drugs and pharmacogenomic associations on culture systems, and guide culture selection for drug tests.

Pancreatic cancer cells may develop resistance to KRAS inhibitors due to activation of compensatory pathways. In this study, the authors demonstrate that KRAS is dispensable in a subset of pancreatic cancer and that PI3K signalling may have an important role in mediating tumor growth following KRAS inhibition.

Ein Schwerpunkt der Aufführungstheorie von Rudolf Kolisch liegt auf der Realisierung der ›richtigen‹ Tempi für Beethovens Musik. In diesem Beitrag wird eine Diskussion über »Aufführungsprobleme im Violinkonzert von Beethoven« von René Leibowitz und Rudolf Kolisch aus dem Jahr 1964 mit der Studioaufnahme des Violinkonzerts durch die beiden Künstler aus demselben Jahr in Zusammenhang gebracht. Voran gestellt ist ein kursorischer Überblick über aktuelle Forschungsliteratur zu diesem Werk, insbesondere im Hinblick auf dessen unkonventionelle Form. Meine eigenen Überlegungen zur formalen Gestaltung des Violinkonzerts widmen sich vor diesem Hintergrund der Frage nach dem Verhältnis von ritornellartiger Wiederkehr und zyklischer Sonatenform. Die sehr langen Tutti-Abschnitte des Werks werfen im Hinblick auf die Aufführung viele Fragen auf, sodass es kein Zufall zu sein scheint, dass gerade Aspekte von Interpretation und Aufführungspraxis in der wissenschaftlichen Literatur zu Beethovens Violinkonzert eine erstaunlich große Rolle spielen. Ein zentrales Ergebnis der vorgenommenen Analyse der Aufnahme Kolischs und Leibowitz’ ist, dass die beiden Künstler in Hinblick auf die Tempogestaltung stärker zwischen Solo- und Tutti-Abschnitten variieren als es die gemeinsame theoretische Diskussion nahelegt. Vermutet werden kann, dass durch diese Tempodisposition die ungewöhnliche Blockhaftigkeit von Beethovens Formgestaltung affirmativ herausgehoben werden sollte. // In Rudolf Kolisch’s theory of performance there is an emphasis on the realization of the ›right‹ tempo in Beethoven’s music. In this article, a discussion between René Leibowitz and Rudolf Kolisch from 1964 about “Aufführungsprobleme im Violinkonzert von Beethoven” (“Problems of Performance in Beethoven’s Violin Concerto”) is contextualized with the studio recording of the violin concerto by the two artists from the same year. This comparison is preceded by an overview of recent analytical literature on the work with an emphasis on its unconventional form. Against this background, my own reflections on the formal concept of the violin concerto focus on the relation of ritornello-like recurrence and cyclic sonata form. Since the long tutti passages in the orchestra pose a challenge to performers, it is no surprise that questions of performance play an important role in analytical studies on the concerto. An important result of the analysis of Kolischʼs and Leibowitzʼs recording is that their tempi in the solo and tutti passages vary more than their theoretical discussion suggests. It may be assumed that this disposition of tempo is used to highlight and to affirm the unusual bloc structure of Beethoven’s formal design.

Formation of the death-inducing signaling complex (DISC) initiates extrinsic apoptosis. Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. By elucidating the function of the caspase-8 homolog, caspase-10, we discover that caspase-10 negatively regulates caspase-8-mediated cell death. Significantly, we reveal that caspase-10 reduces DISC association and activation of caspase-8. Furthermore, we extend our co-operative/hierarchical binding model of caspase-8/cFLIP and show that caspase-10 does not compete with caspase-8 for binding to FADD. Utilizing caspase-8-knockout cells, we demonstrate that caspase-8 is required upstream of both cFLIP and caspase-10 and that DISC formation critically depends on the scaffold function of caspase-8. We establish that caspase-10 rewires DISC signaling to NF-κB activation/cell survival and demonstrate that the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction. Thus, our data are consistent with a model in which both caspase-10 and cFLIP coordinately regulate CD95L-mediated signaling for death or survival.

The larvae of Strophosoma (Strophosoma) capitatum (DeGeer, 1775), S. (Strophosoma) melanogrammum (Forster, 1771) and S. (Neliocarus) sus Stephens, 1831, are illustrated and re-described or described for the first time. The first larval instar, and the mature or an older larval instar, are illustrated, and a general description of the Strophosoma larva is given. The biological data obtained from breeding and field-collecting are compared and discussed in relation to the known life-cycle data.

A 12-year-old, 170 kg, Shetland pony mare was presented with an acute severe right pelvic limb lameness and concurrent upward fixation of the right patella. The affected limb was rotated externally and adducted with a prominent greater trochanter and the right calcaneal tuber being more proximal than its left counterpart. Radiographic examination revealed complete dislocation of the right femoral head from the acetabular cavity in a dorsal and caudal direction. A closed reduction of the coxofemoral luxation was performed successfully under general anaesthesia. A full-body animal rescue and transportation sling (ARTS) was applied for the recovery. The reduction was followed by a right-sided medial patellar desmotomy. The pony was supported in the ARTS for a total of eight weeks combined with crossties for the first six weeks. Subsequently, the mare was discharged with instructions to slowly increase walking exercise over a period of two months before returning to her intended use. A follow-up after 22 months attested the successful treatment of a coxofemoral luxation by closed reduction and prolonged immobilization resulting in a regularly exercised pony without any residual lameness.

Dahlhaus’ Schriften zur Geschichte der Musiktheorie begleiten seine gesamte Publikationstätigkeit. Ähnlich wie in der Musikgeschichte bildet auch in seinen Texten zur Musiktheorie das 19. Jahrhundert einen Schwerpunkt. In dem Beitrag wird zunächst Dahlhaus’ Historiographie der Musiktheorie mit seinem musikhistorischen Hauptwerk Die Musik des 19. Jahrhunderts verglichen. Am Beispiel der Marx’schen Formenlehre und des Antagonismus von Sechter und Riemann soll schließlich exemplarisch dargestellt werden, welche Funktionen theoriegeschichtliche Themen innerhalb von Dahlhaus’ historischem Denken einnehmen. Dahlhaus’ writings on the history of music theory run through his complete publication history. As in his writings on music history, the 19th century similarly figures as a focal point in his writings on the history of music theory. Dahlhaus’ historiography of music theory will be compared in the article with Die Musik des 19. Jahrhunderts, his main publication in music history. Using the examples of Marx’ Formenlehre and the antagonism of Sechter and Riemann, the article will show what function issues in the history of music theory have within Dahlhaus’ historical thinking in general.

Methods to isolate and culture primary prostate epithelial stem/progenitor cells (PESCs) have proven difficult and ineffective. Here, we present a method to grow and expand both murine and human basal PESCs long term in serum- and feeder-free conditions. The method enriches for adherent mouse basal PESCs with a Lin−SCA-1+CD49f+TROP2high phenotype. Progesterone and sodium selenite are additionally required for the growth of human Lin−CD49f+TROP2high PESCs. The gene-expression profiles of expanded basal PESCs show similarities to ESCs, and NF-kB function is critical for epithelial differentiation of sphere-cultured PESCs. When transplanted in combination with urogenital sinus mesenchyme, expanded mouse and human PESCs generate ectopic prostatic tubules, demonstrating their stem cell activity in vivo. This novel method will facilitate the molecular, genomic, and functional characterization of normal and pathologic prostate glands of mouse and human origin.