Mutations in human dynamin block an intermediate stage in coated vesicle formation

The role of human dynamin in receptor-mediated endocytosis was investigated by transient expression of GTP-binding domain mutants in mammalian cells. Using assays which detect intermediates in coated vesicle formation, the dynamin mutants were found to block endocytosis at a stage after the initiation of coat assembly and preceding the sequestration of ligands into deeply invaginated coated pits. Membrane transport from the ER to the Golgi complex was unaffected indicating that dynamin mutants specifically block early events in endocytosis. These results demonstrate that mutations in the GTP-binding domain of dynamin block Tfn-endocytosis in mammalian cells and suggest that a functional dynamin GTPase is required for receptor-mediated endocytosis via clathrin-coated pits

A construction of Frobenius manifolds with logarithmic poles and applications

A construction theorem for Frobenius manifolds with logarithmic poles is established. This is a generalization of a theorem of Hertling and Manin. As an application we prove a generalization of the reconstruction theorem of Kontsevich and Manin for projective smooth varieties with convergent Gromov-Witten potential. A second application is a construction of Frobenius manifolds out of a variation of polarized Hodge structures which degenerates along a normal crossing divisor when certain generation conditions are fulfilled.Comment: 46 page

Morphology of graphene thin film growth on SiC(0001)

Epitaxial films of graphene on SiC(0001) are interesting from a basic physics as well as applications-oriented point of view. Here we study the emerging morphology of in-vacuo prepared graphene films using low energy electron microscopy (LEEM) and angle-resolved photoemission (ARPES). We obtain an identification of single and bilayer of graphene film by comparing the characteristic features in electron reflectivity spectra in LEEM to the PI-band structure as revealed by ARPES. We demonstrate that LEEM serves as a tool to accurately determine the local extent of graphene layers as well as the layer thickness

Diagnostic performance and optimal cut-off scores of the Massachusetts youth screening instrument-second version in a sample of Swiss youths in welfare and juvenile justice institutions

BACKGROUND: There is a growing consensus about the importance of mental health screening of youths in welfare and juvenile justice institutions. The Massachusetts Youth Screening Instrument-second version (MAYSI-2) was specifically designed, normed and validated to assist juvenile justice facilities in the United States of America (USA), in identifying youths with potential emotional or behavioral problems. However, it is not known if the USA norm-based cut-off scores can be used in Switzerland. Therefore, the primary purpose of the current study was to estimate the diagnostic performance and optimal cut-off scores of the MAYSI-2 in a sample of Swiss youths in welfare and juvenile justice institutions. As the sample was drawn from the French-, German- and Italian-speaking parts of Switzerland, the three languages were represented in the total sample of the current study and consequently we could estimate the diagnostic performance and the optimal cut-off scores of the MAYSI-2 for the language regions separately. The other main purpose of the current study was to identify potential gender differences in the diagnostic performance and optimal cut-off scores. METHODS: Participants were 297 boys and 149 girls (mean age = 16.2, SD = 2.5) recruited from 64 youth welfare and juvenile justice institutions (drawn from the French-, German- and Italian-speaking parts of Switzerland). The MAYSI-2 was used to screen for mental health or behavioral problems that could require further evaluation. Psychiatric classification was based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL). The MAYSI-2 scores were submitted into Receiver-Operating Characteristic (ROC) analyses to estimate the diagnostic performance and optimal \u27caution\u27 cut-off scores of the MAYSI-2. RESULTS: The ROC analyses revealed that nearly all homotypic mappings of MAYSI-2 scales onto (cluster of) psychiatric disorders revealed above chance level accuracy. The optimal \u27caution\u27 cut-off scores derived from the ROC curve for predicting (cluster of) psychiatric disorders were, for several MAYSI-2 scales, comparable to the USA norm-based \u27caution\u27 cut-off scores. For some MAYSI-2 scales, however, higher optimal \u27caution\u27 cut-off scores were found. CONCLUSIONS: With adjusted optimal \u27caution\u27 cut-off scores, the MAYSI-2 screens potential emotional or behavioral problems well in a sample of Swiss youths in welfare and juvenile justice institutions. However, as for choosing the optimal \u27caution\u27 cut off score for the MAYSI-2, both language as well as gender seems to be of importance. The results of this study point to a compelling need to test the diagnostic performance and optimal \u27caution\u27 cut-off scores of the MAYSI-2 more elaborately in larger differentiated language samples in Europe

Relationship between Massachusetts Youth Screening Instrument-second version and psychiatric disorders in youths in welfare and juvenile justice institutions in Switzerland

BACKGROUND: There is growing evidence that it is important to have well-standardized procedures for identifying the mental health needs of youths in welfare and juvenile justice institutions. One of the most widely used tools for mental health screening in the juvenile justice system is the Massachusetts Youth Screening Instrument-second version (MAYSI-2). To contribute to the body of research examining the utility of the MAYSI-2 as a mental health screening tool; the first objective of the current study was to examine the relationship between the MAYSI-2 and the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL) in a sample of Swiss youths in welfare and juvenile justice institutions using a cross-sectional design. Secondly, as the sample was drawn from the French-, German- and Italian-speaking parts of Switzerland, the three languages were represented in the total sample and consequently differences between the language regions were analyzed as well. The third objective was to examine gender differences in this relationship. METHODS: Participants were 297 boys and 149 girls (mean age = 16.2, SD = 2.5) recruited from 64 youth welfare and juvenile justice institutions in Switzerland. The MAYSI-2 was used to screen for mental health or behavioral problems that could require further evaluation. Psychiatric classification was based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL). Binomial logistic regression analysis was used to predict (cluster of) psychiatric disorders from MAYSI-2 scales. RESULTS: The regression analyses revealed that the MAYSI-2 scales generally related well to their corresponding homotypic (cluster of) psychiatric disorders. For example, the alcohol/drug use scale identified the presence of any substance use disorder and the suicide ideation scale identified youths reporting suicide ideation or suicide attempts. Several MAYSI-2 scales were also related to heterotypic (cluster of) psychiatric disorders. For example, the MAYSI-2 scale alcohol/drug use, was positively related to any disruptive disorder. Furthermore, the results revealed gender differences in the relationship between the MAYSI-2 and K-SADS-PL (e.g., in the boys\u27 subsample no MAYSI-2 scale was significantly related to any affective disorder; whereas, in the girls\u27 subsample the MAYSI-2 scales depressed-anxious and somatic complaints were significantly related to any affective disorder). CONCLUSIONS: Overall, The MAYSI-2 seems to serve well as a first-stage screen to identify service needs for youths in welfare and juvenile justice institutions in Switzerland. Its effectiveness to identify the presence of (cluster of) psychiatric disorders differs between genders

Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts

Cancer associated fibroblasts (CAFs) play a critical role for growth, invasion, and metastasis of cancer. Therefore, targeting CAFs with small molecule inhibitors may be an attractive anti-tumor strategy. The current study aims to identify small molecule kinase inhibitors affecting CAF's growth and to characterize the biological effects of active compounds on primary CAFs from lung cancer. We screened two individual CAF strains for their sensitivity to a panel of 160 kinase inhibitors. Five kinase inhibitors were identified inhibiting more than 50% of the growth of both cell lines. Three of them were inhibitors of PDGFR at nanomolar concentrations. Therefore, we further tested the FDA approved PDGFR inhibitors Dasatinib, Nilotinib, Sorafenib, and Imatinib. All 37 CAF strains investigated were highly sensitive to Dasatinib at clinically relevant concentrations. Imatinib was slightly less effective, whereas the inhibitory effects of Nilotinib and Sorafenib were significantly less pronounced

A generalized spherical version of the Blume-Emery-Griffits model with ferromagnetic and antiferromagnetic interactions

We have investigated analitycally the phase diagram of a generalized spherical version of the Blume-Emery-Griffiths model that includes ferromagnetic or antiferromagnetic spin interactions as well as quadrupole interactions in zero and nonzero magnetic field. We show that in three dimensions and zero magnetic field a regular paramagnetic-ferromagnetic (PM-FM) or a paramagnetic-antiferromagnetic (PM-AFM) phase transition occurs whenever the magnetic spin interactions dominate over the quadrupole interactions. However, when spin and quadrupole interactions are important, there appears a reentrant FM-PM or AFM-PM phase transition at low temperatures, in addition to the regular PM-FM or PM-AFM phase transitions. On the other hand, in a nonzero homogeneous external magnetic field $H$, we find no evidence of a transition to the state with spontaneous magnetization for FM interactions in three dimensions. Nonethelesss, for AFM interactions we do get a scenario similar to that described above for zero external magnetic field, except that the critical temperatures are now functions of $H$. We also find two critical field values, $H_{c1}$, at which the reentrance phenomenon dissapears and $H_{c2}$ ($H_{c1}\approx 0.5H_{c2}$), above which the PM-AFM transition temperature vanishes.Comment: 21 pages, 6 figs. Title changed, abstract and introduction as well as section IV were rewritten relaxing the emphasis on spin S=1 and Figs. 5 an 6 were improved in presentation. However, all the results remain valid. Accepted for publication in Phys. Rev.

Survival of tumor cells after proton irradiation with ultra-high dose rates

<p>Abstract</p> <p>Background</p> <p>Laser acceleration of protons and heavy ions may in the future be used in radiation therapy. Laser-driven particle beams are pulsed and ultra high dose rates of >10⁹Gy s^-1may be achieved. Here we compare the radiobiological effects of pulsed and continuous proton beams.</p> <p>Methods</p> <p>The ion microbeam SNAKE at the Munich tandem accelerator was used to directly compare a pulsed and a continuous 20 MeV proton beam, which delivered a dose of 3 Gy to a HeLa cell monolayer within < 1 ns or 100 ms, respectively. Investigated endpoints were G2 phase cell cycle arrest, apoptosis, and colony formation.</p> <p>Results</p> <p>At 10 h after pulsed irradiation, the fraction of G2 cells was significantly lower than after irradiation with the continuous beam, while all other endpoints including colony formation were not significantly different. We determined the relative biological effectiveness (RBE) for pulsed and continuous proton beams relative to x-irradiation as 0.91 ± 0.26 and 0.86 ± 0.33 (mean and SD), respectively.</p> <p>Conclusions</p> <p>At the dose rates investigated here, which are expected to correspond to those in radiation therapy using laser-driven particles, the RBE of the pulsed and the (conventional) continuous irradiation mode do not differ significantly.</p

Parameter Estimation of Ion Current Formulations Requires Hybrid Optimization Approach to Be Both Accurate and Reliable

Computational models of cardiac electrophysiology provided insights into arrhythmogenesis and paved the way toward tailored therapies in the last years. To fully leverage in silico models in future research, these models need to be adapted to reflect pathologies, genetic alterations, or pharmacological effects, however. A common approach is to leave the structure of established models unaltered and estimate the values of a set of parameters. Today’s high-throughput patch clamp data acquisition methods require robust, unsupervised algorithms that estimate parameters both accurately and reliably. In this work, two classes of optimization approaches are evaluated: gradient-based trust-region-reflective and derivative-free particle swarm algorithms. Using synthetic input data and different ion current formulations from the Courtemanche et al. electrophysiological model of human atrial myocytes, we show that neither of the two schemes alone succeeds to meet all requirements. Sequential combination of the two algorithms did improve the performance to some extent but not satisfactorily. Thus, we propose a novel hybrid approach coupling the two algorithms in each iteration. This hybrid approach yielded very accurate estimates with minimal dependency on the initial guess using synthetic input data for which a ground truth parameter set exists. When applied to measured data, the hybrid approach yielded the best fit, again with minimal variation. Using the proposed algorithm, a single run is sufficient to estimate the parameters. The degree of superiority over the other investigated algorithms in terms of accuracy and robustness depended on the type of current. In contrast to the non-hybrid approaches, the proposed method proved to be optimal for data of arbitrary signal to noise ratio. The hybrid algorithm proposed in this work provides an important tool to integrate experimental data into computational models both accurately and robustly allowing to assess the often non-intuitive consequences of ion channel-level changes on higher levels of integration

Transport Anomalies and Marginal Fermi-Liquid Effects at a Quantum Critical Point

The conductivity and the tunneling density of states of disordered itinerant electrons in the vicinity of a ferromagnetic transition at low temperature are discussed. Critical fluctuations lead to nonanalytic frequency and temperature dependences that are distinct from the usual long-time tail effects in a disordered Fermi liquid. The crossover between these two types of behavior is proposed as an experimental check of recent theories of the quantum ferromagnetic critical behavior. In addition, the quasiparticle properties at criticality are shown to be those of a marginal Fermi liquid.Comment: 4pp., REVTeX, no figs, final version as publishe