Murine terminal deoxynucleotidyl transferase: cellular distribution and response to cortisone

The mouse thymus contains two forms of terminal deoxynucleotidyl transferase (TdT) which are distinguishable by the salt concentration necessary to elute them from a phosphocellulose column, by their distrubtion among the thymocyte subpopulations, and by their sensitivity to cortisone treatment. In the whole thymus the later eluting peak (peak II) is the predominant one with about 3-10% of the total activity appearing in peak I. Both peak I and peak II activities are most sensitively assayed by the polymerization of dGMP onto an oligo(dA) primer. The minor population of thymocytes which is less dense and cortisone-resistant contains a higher specific activity of peak I TdT. The majority of TdT activity is, however, found in the major population of thymocytes which occurs in the center region of a bovine serum albumin gradient and is cortisone-sensitive. A very low level of an activity indistinguishable from peak II TdT activity is also detected in the mouse bone marrow. Other tissues, such as spleen, liver, heart, and brain lack detectable amounts of TdT activity

Doping evolution of spin and charge excitations in the Hubbard model

To shed light on how electronic correlations vary across the phase diagram of the cuprate superconductors, we examine the doping evolution of spin and charge excitations in the single-band Hubbard model using determinant quantum Monte Carlo (DQMC). In the single-particle response, we observe that the effects of correlations weaken rapidly with doping, such that one may expect the random phase approximation (RPA) to provide an adequate description of the two-particle response. In contrast, when compared to RPA, we find that significant residual correlations in the two-particle excitations persist up to $40\%$ hole and $15\%$ electron doping (the range of dopings achieved in the cuprates). These fundamental differences between the doping evolution of single- and multi-particle renormalizations show that conclusions drawn from single-particle processes cannot necessarily be applied to multi-particle excitations. Eventually, the system smoothly transitions via a momentum-dependent crossover into a weakly correlated metallic state where the spin and charge excitation spectra exhibit similar behavior and where RPA provides an adequate description.Comment: 5 pages, 4 figures, plus supplementary materia

Survival of Hendra Virus in the Environment: Modelling the Effect of Temperature

Hendra virus (HeV), a highly pathogenic zoonotic paramyxovirus recently emerged from bats, is a major concern to the horse industry in Australia. Previous research has shown that higher temperatures led to lower virus survival rates in the laboratory. We develop a model of survival of HeV in the environment as influenced by temperature. We used 20 years of daily temperature at six locations spanning the geographic range of reported HeV incidents to simulate the temporal and spatial impacts of temperature on HeV survival. At any location, simulated virus survival was greater in winter than in summer, and in any month of the year, survival was higher in higher latitudes. At any location, year-to-year variation in virus survival 24 h post-excretion was substantial and was as large as the difference between locations. Survival was higher in microhabitats with lower than ambient temperature, and when environmental exposure was shorter. The within-year pattern of virus survival mirrored the cumulative within-year occurrence of reported HeV cases, although there were no overall differences in survival in HeV case years and non-case years. The model examines the effect of temperature in isolation; actual virus survivability will reflect the effect of additional environmental factor

Survival of Hendra Virus in the Environment: Modelling the Effect of Temperature

Hendra virus (HeV), a highly pathogenic zoonotic paramyxovirus recently emerged from bats, is a major concern to the horse industry in Australia. Previous research has shown that higher temperatures led to lower virus survival rates in the laboratory. We develop a model of survival of HeV in the environment as influenced by temperature. We used 20 years of daily temperature at six locations spanning the geographic range of reported HeV incidents to simulate the temporal and spatial impacts of temperature on HeV survival. At any location, simulated virus survival was greater in winter than in summer, and in any month of the year, survival was higher in higher latitudes. At any location, year-to-year variation in virus survival 24 h post-excretion was substantial and was as large as the difference between locations. Survival was higher in microhabitats with lower than ambient temperature, and when environmental exposure was shorter. The within-year pattern of virus survival mirrored the cumulative within-year occurrence of reported HeV cases, although there were no overall differences in survival in HeV case years and non-case years. The model examines the effect of temperature in isolation; actual virus survivability will reflect the effect of additional environmental factor

The failure of stellar feedback, magnetic fields, conduction, and morphological quenching in maintaining red galaxies

The quenching "maintenance'" and related "cooling flow" problems are important in galaxies from Milky Way mass through clusters. We investigate this in halos with masses $\sim 10^{12}-10^{14}\,{\rm M}_{\odot}$, using non-cosmological high-resolution hydrodynamic simulations with the FIRE-2 (Feedback In Realistic Environments) stellar feedback model. We specifically focus on physics present without AGN, and show that various proposed "non-AGN" solution mechanisms in the literature, including Type Ia supernovae, shocked AGB winds, other forms of stellar feedback (e.g. cosmic rays), magnetic fields, Spitzer-Braginskii conduction, or "morphological quenching" do not halt or substantially reduce cooling flows nor maintain "quenched" galaxies in this mass range. We show that stellar feedback (including cosmic rays from SNe) alters the balance of cold/warm gas and the rate at which the cooled gas within the galaxy turns into stars, but not the net baryonic inflow. If anything, outflowing metals and dense gas promote additional cooling. Conduction is important only in the most massive halos, as expected, but even at $\sim 10^{14}\,{\rm M}_{\odot}$ reduces inflow only by a factor $\sim 2$ (owing to saturation effects and anisotropic suppression). Changing the morphology of the galaxies only slightly alters their Toomre-$Q$ parameter, and has no effect on cooling (as expected), so has essentially no effect on cooling flows or maintaining quenching. This all supports the idea that additional physics, e.g., AGN feedback, must be important in massive galaxies.Comment: 16 pages, 12 figure

Discrete Effects in Stellar Feedback: Individual Supernovae, Hypernovae, and IMF Sampling in Dwarf Galaxies

Using high-resolution simulations from the FIRE-2 (Feedback In Realistic Environments) project, we study the effects of discreteness in stellar feedback processes on the evolution of galaxies and the properties of the interstellar medium (ISM). We specifically consider the discretization of supernovae (SNe), including hypernovae (HNe), and sampling the initial mass function (IMF). We study these processes in cosmological simulations of dwarf galaxies with $z=0$ stellar masses $M_{\ast}\sim 10^{4}-3\times10^{6}\,M_\odot$ (halo masses $\sim 10^{9}-10^{10}\,M_\odot$). We show that the discrete nature of individual SNe (as opposed to a model in which their energy/momentum deposition is continuous over time, similar to stellar winds) is crucial in generating a reasonable ISM structure and galactic winds and in regulating dwarf stellar masses. However, once SNe are discretized, accounting for the effects of IMF sampling on continuous mechanisms such as radiative feedback and stellar mass-loss (as opposed to adopting IMF-averaged rates) has weak effects on galaxy-scale properties. We also consider the effects of rare HNe events with energies $\sim 10^{53}\,{\rm erg}$. The effects of HNe are similar to the effects of clustered explosions of SNe -- which are already captured in our default simulation setup -- and do not quench star formation (provided that the HNe do not dominate the total SNe energy budget), which suggests that HNe yield products should be observable in ultra-faint dwarfs today.Comment: 9 pages, 4 figure

Global-Local Finite Element Analysis

114 σ.Η αναλυτική επίλυση πολύπλοκων προβλημάτων της μηχανικής στις μέρες μας καθίσταται δυσχερής εως αδύνατη χωρίς την εφαρμογή αριθμητικών μεθόδων και τη χρήση ηλεκτρονικού υπολογιστή. Η μέθοδος των πεπερασμένων στοιχείων αποτελεί σήμερα ένα ισχυρό εργαλείο για την επίλυση τέτοιων προβλημάτων και εξελίσσεται με μεγάλη ταχύτητα τόσο σε ακαδημαϊκό όσο και σε επαγγελματικό επίπεδο. Ενδεικτικά, αν και επινοήθηκε και χρησιμοποιήθηκε για τη στατική ανάλυση φορέων, έχει καθολικότερη εφαρμογή σε μια ευρύτερη κατηγορία προβλημάτων του μηχανικού, όπως στη ρευστομηχανική, στη μεταφορά θερμότητας, στην ακουστική, στον ηλεκτρομαγνητισμό και στην εμβιομηχανική. Επιπλέον, η εξέλιξη στων Η/Υ με τις ολοένα μεγαλύτερες δυνατότητες διαχείρισης όγκου δεδομένων αλλά και με την αύξηση της ταχύτητας εκτέλεσης των αριθμητικών πράξεων κατέστησε εφικτή την επίλυση σύνθετων προβλημάτων τα οποία θεωρούνταν απροσπέλαστα πριν μερικά χρόνια. Στην κατηγορία αυτή, των προβλημάτων αυξημένου υπολογιστικού κόστους, ανήκει και η καταστατική περιγραφή πολυφασικών υλικών. Είναι γεγονός ότι το μεγαλύτερο μέρος των παραγώμενων δομικών υλικών σήμερα, παρουσιάζει κάποιο είδος ανομοιογένειας, διακριτή ή μη στην κλίμακα δομικών έργων. Χαρακτηριστικά παραδείγματα αποτελούν τα κράματα μετάλλων, τα πορώδη, τα πολυκρυσταλλικά και τα σύνθετα υλικά στα οποία το μέγεθος, το σχήμα και οι ιδιότητες των συστατικών τους μερών καθορίζουν άμεσα τη συνολική τους μηχανική συμπεριφορά. Διάφορες τεχνικές έχουν αναπτυχθεί για την προσομοίωση και την περιγραφή της απόκρισης ανομοιογενών υλικών. Η παρούσα εργασία επικεντρώνεται στη μέθοδο ομογενοποίησης πολλαπλών κλιμάκων η οποία συνίσταται στην επίλυση δύο εμφωλευμένων προβλημάτων συνοριακών τιμών, για τη μακροκλίμακα και τη μικροκλίμακα αντίστοιχα. Τα βασικά χαρακτηριστικά μιας τέτοιας μεθόδου είναι ότι - Δεν απαιτείται η περιγραφή των καταστατικών νόμων του μακροφορέα. - Παρέχει τη δυνατότητα ενσωμάτωσης μεγάλων παραμορφώσεων και στροφών τόσο στην προσομοίωση της μικροκλίμακας όσο και του μακροφορέα. - Παρέχει τη δυνατότητα λεπτομερούς προσομοίωσης των συστατικών μερών της μικροκλίμακας. - Επιτρέπει οποιαδήποτε τεχνική επίλυσης στην κλίμακα του μικροφορέα. Αναλυτικά, σύμφωνα με τη μέθοδο αυτή. υπολογίζεται το διάνυσμα ανηγμένων παραμορφώσεων σε κάθε υλικό σημείο του μακροφορέα το οποίο στη συνέχεια χρησιμοποιείται για τη μόρφωση των συνοριακών συνθηκών του αντιπροσωπευτικού μικροφορέα στο αντίστοιχο σημείο. Μετά την επίλυση του προβλήματος συνοριακών τιμών της μικροκλίμακας, το διάνυσμα των τάσεων του μακροφορέα υπολογίζεται μέσα από τη διαδικασία ομογενοποίησης του πεδίου των τάσεων και κατά τον τρόπο αυτό υπολογίζεται η σχέση τάσεων ανηγμένων παραμορφώσεων για κάθε υλικό σημείο Ωστόσο, υπάρχουν κάποιοι περιορισμοί στην εφαρμογή της εν λόγω υπολογιστικής τεχνικής. Συγκεκριμένα, παρά το ότι κατά την προσομοίωση λαμβάνονται υπ' όψην οι διάφορες παράμετροι της μικροκλίμακας όπως το ποσοστό όγκου, η κατανομή και η μορφολογία των συστατικών μερών του υλικού, τα αποτελέσματα της μεθόδου είναι ανεξάρτητα από το απόλυτο μέγεθος του αντιπροσωπευτικού όγκου της μικροκλίμακας. Παρ' όλα αυτά, η τεχνική ομογενοποίησης στα πλαίσια ανάλυσης πολλαπλών κλιμάκων αποτελεί ένα σημαντικό εργαλείο για τον υπολογισμό των καταστατικών σχέσεων πολυφασικών υλικών στα οποία είναι αδύνατη η εφαρμογή οποιασδήποτε άλλης μεθόδου.Nowadays, analysis of complicated problems in the domain of mechanics consti- tutes a hard and even impossible task without the implementation of numerical methods and the employment of computational machines. Finite element method is a powerful tool for the solution of such problems and is rapidly developed in an academic and professional sense. Even if it was developed and implemented for structural analysis, it is widely employed in several domains such as in fluid mechanics, heat transfer, acoustics and electromagnetism. Furthermore, the development of computer hardware in terms of data processing, has significantly contributed to the solution of problems that were considered inaccessible a few years ago. Most of the materials produced in industry are heterogeneous on one or another spatial scale. Typical examples include metal alloy systems, porous media and polycrystalline materials and composites. The overall response of these micro heterogeneous materials depends strongly on the size, shape properties and spatial distribution of the microstructural components. Several techniques have been developed for the prediction of the macroscopic behavior of such materials. The present work is concentrated on the first order homogenization technique in the framework of a multi-scale approach which consists of the solution of two nested boundary value problems, for the macro-scale and the micro-scale respectively. Methods of this type - Do not require any constitutive assumption with respect to the overall ma- terial behavior. - Enable the incorporation of large deformations and rotations on both micro and macrolevel. - Provide the possibility to introduce detailed microstructural information. - Allow the use of any modelling technique at the microlevel. Concretely, according to this approach, the macroscopic deformation tensor is calculated for every integration point of the macrostructure and then is used to formulate the kinematic boundary conditions for the associated microstructural representative volume element (RVE). After the solution of the microstructural boundary value problem, the macroscopic stress tensor is computed by averaging the resulting microstructural stress field over the volume of the RVE and as a result, we obtain the stress-strain relation at every macroscopic point. However, there is a major disadvantage of the existing first-order computational homogenization. More specifically, this technique can account for the volume fraction, distribution and morphology of the micro-components however, it cannot take into account the absolute size of the microstructure making it thus impossible to treat microstructural size effects. Nevertheless, computational homogenization provides a significant strategy to obtain micro-macro structure-property relations for materials for which the overall macroscopic response cannot be computed by any other method.Κωνσταντινος Ε. Τατση

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor.

Btk and Etk/BMX are Tec-family non-receptor tyrosine kinases. Btk has previously been reported to be expressed primarily in B cells and has an important role in immune responses and B-cell malignancies. Etk has been shown previously to provide a strong survival and metastasis signal in human prostate cancer cells, and to confer androgen independence and drug resistance. While the role of Etk in prostate carcinogenesis is well established, the functions of Btk in prostate cancer have never been investigated, likely due to the perception that Btk is a hematopoietic, but not epithelial, kinase. Herein, we found that Btk is overexpressed in prostate cancer tissues and prostate cancer cells. The level of Btk in prostate cancer tissues correlates with cancer grades. Knockdown of Btk expression selectively inhibits the growth of prostate cancer cells, but not that of the normal prostate epithelial cells, which express very little Btk. Dual inhibition of Btk and Etk has an additive inhibitory effect on prostate cancer cell growth. To explore Btk and Etk as targets for prostate cancer, we developed a small molecule dual inhibitor of Btk and Etk, CTN06. Treatment of PC3 and other prostate cancer cells, but not immortalized prostate epithelial cells with CTN06 resulted in effective cell killing, accompanied by the attenuation of Btk/Etk signals. The killing effect of CTN06 is more potent than that of commonly used inhibitors against Src, Raf/VEGFR and EGFR. CTN06 induces apoptosis as well as autophagy in human prostate cancer cells, and is a chemo-sensitizer for docetaxel (DTX), a standard of care for metastatic prostate cancer patients. CTN06 also impeded the migration of human prostate cancer cells based on a 'wound healing' assay. The anti-cancer effect of CTN06 was further validated in vivo in a PC3 xenograft mouse model