A Combination of screening and computational approaches for the identification of novel compounds that decrease mast cell degranulation

High-content screening of compound libraries poses various challenges in the early steps in drug discovery such as gaining insights into the mode of action of the selected compounds. Here, we addressed these challenges by integrating two biological screens through bioinformatics and computational analysis. We screened a small-molecule library enriched in amphiphilic compounds in a degranulation assay in rat basophilic leukemia 2H3 (RBL-2H3) cells. The same library was rescreened in a high-content image-based endocytosis assay in HeLa cells. This assay was previously applied to a genome-wide RNAi screen that produced quantitative multiparametric phenotypic profiles for genes that directly or indirectly affect endocytosis. By correlating the endocytic profiles of the compounds with the genome-wide siRNA profiles, we identified candidate pathways that may be inhibited by the compounds. Among these, we focused on the Akt pathway and validated its inhibition in HeLa and RBL-2H3 cells. We further showed that the compounds inhibited the translocation of the Akt-PH domain to the plasma membrane. The approach performed here can be used to integrate chemical and functional genomics screens for investigating the mechanism of action of compounds

Archaeological Geophysical Prospection in Peatland Environments: case studies and suggestions for future practice

Peatland environments, in contrast to ‘dry-land’ sites, preserve organic material, including anthropogenic objects, because they are anaerobic, and are therefore of great importance to archaeology. Peat also preserves macro- and micro- paleoenvironmental evidence and is the primary resource for understanding past climates and ecology. Archaeological sites often lie within or at the base of wet, deep, homogenous peat rendering them invisible to surface observers. As a result, they most often c..

Emerging from the third space chrysalis: Experiences in a non-hierarchical, collaborative research community of practice

This article discusses the creation of a research-focused virtual community of practice (vCoP) for geographically-dispersed third space professionals, motivated by desires for enhanced professional collaboration, visibility and identity. The authors used collaborative autoethnography (CAE) to evaluate their personal reflections as vCoP participants. Data were gathered in two collaborative writing activities and analysed using thematic analysis (TA). The TA identified two connected themes, which capture the vCoP members’ aspirations to transcend their current roles and be research-active through connecting with like-minded professionals. Collaborative writing activities, including authoring this paper, cultivated elements of academic identity such as independence and purpose. A non-hierarchical and supportive vCoP environment allowed the members to work beyond time and institutional constraints to foster the evolution of the community and an emerging sense of professional identity beyond that typically associated with third space roles. The paper offers a model of collaboration that could help groups in similar situations

Emerging from the third space chrysalis: Experiences in a non-hierarchical, collaborative research community of practice

This article discusses the creation of a research-focused virtual community of practice (vCoP) for geographically-dispersed third space professionals, motivated by desires for enhanced professional collaboration, visibility and identity. The authors used collaborative autoethnography (CAE) to evaluate their personal reflections as vCoP participants. Data were gathered in two collaborative writing activities and analysed using thematic analysis (TA). The TA identified two connected themes, which capture the vCoP members’ aspirations to transcend their current roles and be research-active through connecting with like-minded professionals. Collaborative writing activities, including authoring this paper, cultivated elements of academic identity such as independence and purpose. A non-hierarchical and supportive vCoP environment allowed the members to work beyond time and institutional constraints to foster the evolution of the community and an emerging sense of professional identity beyond that typically associated with third space roles. The paper offers a model of collaboration that could help groups in similar situations. Practitioner Notes 1. Virtual Communities of Practice (vCoPs) can help geographically-dispersed third space, or other higher education professionals connect with like-minded colleagues to meet common aspirations and cultivate a sense of shared professional identity. 2. Democratic participation and support from fellow vCoP members promote commitment, creative thinking, motivation and an openness to generating ideas and trying new ways of working 3. Shared activities, such as collaborative writing and reflection, allow a virtual group to work within time and institutional constraints in ways that would not be achievable for each individual working alone. Such collaboration fosters the evolution of the community 4. The model of collaboration developed by this particular vCoP could be used by other groups to address questions in the changing HE landscape that are relevant to them, and plan activities to strengthen their vCoP’s group identity. 5. Collaborative autoethnography is an appropriate methodology to research a particular cultural and communal context where participants act as both the subjects and the researchers

Responsibility and appropriate blame: The no difference view

How do the fact that an agent is morally responsible for a certain morally objectionable action and the fact that she is an appropriate target of blame for it relate to each other? Many authors inspired by Peter Strawson say that they necessarily co‐occur. Standard answers to the question of why they co‐occur say that the occurrence of one of the facts explains that the other obtains. This article presents a third option: that they are one and the same fact. There is no difference between the fact that a person is an appropriate target of blame for an objectionable action and the fact that she is morally responsible for it. This view has the advantage of being metaphysically more parsimonious and of answering, in an elegant and plausible way, an interesting question about which many standard theories of responsibility keep silent: what is it to be morally responsible simpliciter

Observational evidence confirms modelling of the long-term integrity of CO2-reservoir caprocks

Anthropogenic CO2 storage, where CO2 is injected into saline geological resevoirs, relies on an impermeable caprock to seal in the CO2, but caprock reaction rates to CO2 acid brines are unclear

Association of growth with neurodevelopment in extremely low gestational age infants: a population-based analysis.

To assess the association between postnatal growth and neurodevelopment at the age of 2 years in extremely low gestational age newborns (ELGAN, < 28 weeks' gestation). Retrospective population-based cohort study including all live born ELGAN in 2006-2012 in Switzerland. Growth parameters (weight, length, head circumference, body mass index) were assessed at birth, at hospital discharge home, and 2-year follow-up (FU2). Unadjusted and adjusted regression models assessed associations between growth (birth to hospital discharge and birth to FU2) and neurodevelopment at FU2. A total of 1244 infants (mean GA 26.5 ± 1.0 weeks, birth weight 853 ± 189 g) survived to hospital discharge and were included in the analyses. FU2 was documented for 1049 (84.3%) infants. The mean (± SD) mental and a psychomotor development index at 2FU were 88.9 (± 18.0) and 86.9 (± 17.7), respectively. Moderate or severe neurodevelopmental impairment was documented in 23.2% of patients. Changes of z-scores between birth and discharge and between birth and FU2 for weight were - 1.06 (± 0.85) and - 0.140 (± 1.15), for length - 1.36 (± 1.34), and - 0.40 (± 1.33), for head circumference - 0.61 (± 1.04) and - 0.76 (± 1.32) as well as for BMI 0.22 (± 3.36) and - 0.006 (± 1.45). Unadjusted and adjusted analyses showed that none of the four growth parameters was significantly associated with any of the three outcome parameters of neurodevelopment. This was consistent for both time intervals. CONCLUSION In the present population-based cohort of ELGAN, neither growth between birth and hospital discharge nor between birth and FU2 were significantly associated with neurodevelopment at age of 2 years. WHAT IS KNOWN • Studies assessing the association between growth and neurodevelopment in extremely low gestational age newborns (28 weeks' gestation) show conflicting results. WHAT IS NEW • Neither growth between birth and hospital discharge nor between birth and corrected age of 2 years were significantly associated with neurodevelopment at age of 2 years. • The role of postnatal growth as a predictor of neurodevelopmental outcome during infancy might be smaller than previously assumed

Long-Term Potentiation: One Kind or Many?

Do neurobiologists aim to discover natural kinds? I address this question in this chapter via a critical analysis of classification practices operative across the 43-year history of research on long-term potentiation (LTP). I argue that this 43-year history supports the idea that the structure of scientific practice surrounding LTP research has remained an obstacle to the discovery of natural kinds