In vitro maturation of immature thymocytes into immunocompetent T cells in the absence of direct thymic influence

Peanut lectin (PNL) binds to a majority of mouse thymocytes (Thc) in suspension. By using cell affinity chromatography on a column of anti-PNL antibody, Thc populations at least 96 percent pure in PNL + or - cells, as judged by immunofluorescence, were obtained. PNL(+) cells are rich in Thy 1 and poor in H(2) antigens, cortisone sensitive, unresponsive to phytohemagglutinin (PHA), and immunologically incompetent, as judged by mixed lymphocyte reaction, popliteal lymph node graft-versus-host assay, and by testing helper activity in a primary in vitro antibody response to sheep erythrocytes; the converse is true of PNL(-) cells. Thus, PNL(+) and (-) cells appear to correspond to cortical and medullary Thc, respectively, as previously suggested. In culture, PNL(+) Thc show poor viability and a weak proliferative response to concanavalin A (Con A), except when supernate (SUP) of 24 h Con A stimulated lymph node lymphocyte cultures, or irradiated lymph node cells, are added, in which cases a strong proliferative response to the mitogen is observed. A variety of control experiments showed that the proliferating cells did not result from preferential stimulation of a few contaminating PNL(-) Thc present in the PNL(+) Thc cultures. The blasts resulting from PNL(+) Thc proliferation display mitogen-induced cytotoxicity, and give rise to a population of medium-sized lymphocytes, mostly PNL(-), poor in Thy 1 and rich in H(2) antigens, PHA responsive, and immunologically competent in the above-mentioned assays. Fresh PNL(+) Thc responded in mixed lymphocyte reaction in the presence of SUP (lectin depleted) and since incubation in SUP alone did not confer reactivity on PNL(+) Thc, it appears therefore that (a) immature Thc possess alloantigen and mitogen-specific surface receptors but lack the capacity to respond by proliferation to receptor triggering without the help of extracellular factor(s) released by mature lymphoid cells stimulated by mitogens (b) cell division is associated with the acquisition of immunological responsiveness, characteristic of mature T lymphocytes. The implications of these findings for the ontogenesis of thymus-derived lymphocytes, and for the possible traffic of Thc within and from the thymus, are discussed

Optimising the data combination rule for seamless phase II/III clinical trials

We consider seamless Phase II/III clinical trials which compare K treatments with a common control in Phase II, then test the most promising treatment against control in Phase III. The final hypothesis test for the selected treatment can use data from both Phases, subject to controlling the familywise type I error rate. We show that the choice of method for conducting the final hypothesis test has a substantial impact on the power to demonstrate that an effective treatment is superior to control. To understand these differences in power we derive optimal decision rules, maximising power for particular configurations of treatment effects. Rules with optimal frequentist properties are found as solutions to multivariate Bayes decision problems. Although the optimal rule depends on the configuration of treatment means considered, we are able to identify two decision rules with robust efficiency: a rule using a weighted average of the Phase II and Phase III data on the selected treatment and control, and a closed testing procedure using an inverse normal combination rule and a Dunnett test for intersection hypotheses. For the first of these rules, we find the optimal division of a given total sample size between Phase II and Phase III.We also assess the value of using Phase II data in the final analysis and find that for many plausible scenarios, between 50% and 70% of the Phase II numbers on the selected treatment and control would need to be added to the Phase III sample size in order to achieve the same increase in power

DFTB+, a software package for efficient approximate density functional theory based atomistic simulations

DFTB+ is a versatile community developed open source software package offering fast and efficient methods for carrying out atomistic quantum mechanical simulations. By implementing various methods approximating density functional theory (DFT), such as the density functional based tight binding (DFTB) and the extended tight binding method, it enables simulations of large systems and long timescales with reasonable accuracy while being considerably faster for typical simulations than the respective ab initio methods. Based on the DFTB framework, it additionally offers approximated versions of various DFT extensions including hybrid functionals, time dependent formalism for treating excited systems, electron transport using non-equilibrium Green's functions, and many more. DFTB+ can be used as a user-friendly standalone application in addition to being embedded into other software packages as a library or acting as a calculation-server accessed by socket communication. We give an overview of the recently developed capabilities of the DFTB+ code, demonstrating with a few use case examples, discuss the strengths and weaknesses of the various features, and also discuss on-going developments and possible future perspectives

Internet-based guided self-help for glioma patients with depressive symptoms: a randomized controlled trial

Depressive symptoms are common in glioma patients, and can negatively affect health-related quality of life (HRQOL). We performed a nation-wide randomized controlled trial to evaluate the effects of an online guided self-help intervention for depressive symptoms in adult glioma patients. Glioma patients with depressive symptoms were randomized to a 5-week online course based on problem-solving therapy, or a waiting list control group. After having received the intervention, the glioma patient groups combined were compared with patients with cancer outside the central nervous system (non-CNS cancer controls), who also received the intervention. Sample size calculations yielded 63 participants to be recruited per arm. The primary outcome [depressive symptoms (CES-D)] and secondary outcomes [fatigue (Checklist Individual Strength (CIS)) and HRQOL (Short Form-36)], were assessed online at baseline, post-intervention, and 3 and 12 months follow-up. In total, 89 glioma patients (intervention N = 45; waiting list N = 44) and 26 non-CNS cancer controls were included, of whom 35 and 54% completed the intervention, respectively. Recruitment could not be extended beyond 3.5 years due to funding. On depression, no statistically significant differences between the groups were found. Fatigue decreased post-treatment in the glioma intervention group compared with the waiting list group (p = 0.054, d = 0.306). At 12 months, the physical component summary (HRQOL) remained stable in glioma patients, while scores improved in non-CNS cancer controls (p = 0.035, d = 0.883). In this underpowered study, no evidence for the effectiveness of online guided self-help for depression or HRQOL in glioma patients was found, but it may improve fatigue

Self-organization of developing embryo using scale-invariant approach

<p>Abstract</p> <p>Background</p> <p>Self-organization is a fundamental feature of living organisms at all hierarchical levels from molecule to organ. It has also been documented in developing embryos.</p> <p>Methods</p> <p>In this study, a scale-invariant power law (SIPL) method has been used to study self-organization in developing embryos. The SIPL coefficient was calculated using a centro-axial skew symmetrical matrix (CSSM) generated by entering the components of the Cartesian coordinates; for each component, one CSSM was generated. A basic square matrix (BSM) was constructed and the determinant was calculated in order to estimate the SIPL coefficient. This was applied to developing <it>C. elegans </it>during early stages of embryogenesis. The power law property of the method was evaluated using the straight line and Koch curve and the results were consistent with fractal dimensions (fd). Diffusion-limited aggregation (DLA) was used to validate the SIPL method.</p> <p>Results and conclusion</p> <p>The fractal dimensions of both the straight line and Koch curve showed consistency with the SIPL coefficients, which indicated the power law behavior of the SIPL method. The results showed that the ABp sublineage had a higher SIPL coefficient than EMS, indicating that ABp is more organized than EMS. The fd determined using DLA was higher in ABp than in EMS and its value was consistent with type 1 cluster formation, while that in EMS was consistent with type 2.</p

Resolving the neural circuits of anxiety

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIH Director’s New Innovator Award DP2-DK-102256-01)National Institute of Mental Health (U.S.) (NIH) R01-MH102441-01)JPB Foundatio

Laser Interactions for the Synthesis and In Situ Diagnostics of Nanomaterials

Laser interactions have traditionall been at thec center of nanomaterials science, providing highly nonequilibrium growth conditions to enable the syn- thesis of novel new nanoparticles, nanotubes, and nanowires with metastable phases. Simultaneously, lasers provide unique opportunities for the remote char- acterization of nanomaterial size, structure, and composition through tunable laser spectroscopy, scattering, and imaging. Pulsed lasers offer the opportunity, there- fore, to supply the required energy and excitation to both control and understand the growth processes of nanomaterials, providing valuable views of the typically nonequilibrium growth kinetics and intermediates involved. Here we illustrate the key challenges and progress in laser interactions for the synthesis and in situ diagnostics of nanomaterials through recent examples involving primarily carbon nanomaterials, including the pulsed growth of carbon nanotubes and graphene