21 research outputs found
Rapid Sampling of Molecular Motions with Prior Information Constraints
Proteins are active, flexible machines that perform a range of different
functions. Innovative experimental approaches may now provide limited partial
information about conformational changes along motion pathways of proteins.
There is therefore a need for computational approaches that can efficiently
incorporate prior information into motion prediction schemes. In this paper, we
present PathRover, a general setup designed for the integration
of prior information into the motion planning algorithm of rapidly exploring
random trees (RRT). Each suggested motion pathway comprises a sequence of
low-energy clash-free conformations that satisfy an arbitrary number of prior
information constraints. These constraints can be derived from experimental data
or from expert intuition about the motion. The incorporation of prior
information is very straightforward and significantly narrows down the vast
search in the typically high-dimensional conformational space, leading to
dramatic reduction in running time. To allow the use of state-of-the-art energy
functions and conformational sampling, we have integrated this framework into
Rosetta, an accurate protocol for diverse types of structural modeling. The
suggested framework can serve as an effective complementary tool for molecular
dynamics, Normal Mode Analysis, and other prevalent techniques for predicting
motion in proteins. We applied our framework to three different model systems.
We show that a limited set of experimentally motivated constraints may
effectively bias the simulations toward diverse predicates in an outright
fashion, from distance constraints to enforcement of loop closure. In
particular, our analysis sheds light on mechanisms of protein domain swapping
and on the role of different residues in the motion
Structural Intermediates in a Model of the Substrate Translocation Path of the Bacterial Glutamate Transporter Homologue GltPh
Apoptosis of Purified CD4+ T Cell Subsets Is Dominated by Cytokine Deprivation and Absence of Other Cells in New Onset Diabetic NOD Mice
BACKGROUND: Regulatory T cells (Treg) play a significant role in immune homeostasis and self-tolerance. Excessive sensitivity of isolated Treg to apoptosis has been demonstrated in NOD mice and humans suffering of type 1 diabetes, suggesting a possible role in the immune dysfunction that underlies autoimmune insulitis. In this study the sensitivity to apoptosis was measured in T cells from new onset diabetic NOD females, comparing purified subsets to mixed cultures. PRINCIPAL FINDINGS: Apoptotic cells are short lived in vivo and death occurs primarily during isolation, manipulation and culture. Excessive susceptibility of CD25(+) T cells to spontaneous apoptosis is characteristic of isolated subsets, however disappears when death is measured in mixed splenocyte cultures. In variance, CD25(-) T cells display balanced sensitivity to apoptosis under both conditions. The isolation procedure removes soluble factors, IL-2 playing a significant role in sustaining Treg viability. In addition, pro- and anti-apoptotic signals are transduced by cell-to-cell interactions: CD3 and CD28 protect CD25(+) T cells from apoptosis, and in parallel sensitize naïve effector cells to apoptosis. Treg viability is modulated both by other T cells and other subsets within mixed splenocyte cultures. Variations in sensitivity to apoptosis are often hindered by fast proliferation of viable cells, therefore cycling rates are mandatory to adequate interpretation of cell death assays. CONCLUSIONS: The sensitivity of purified Treg to apoptosis is dominated by cytokine deprivation and absence of cell-to-cell interactions, and deviate significantly from measurements in mixed populations. Balanced sensitivity of naïve/effector and regulatory T cells to apoptosis in NOD mice argues against the concept that differential susceptibility affects disease evolution and progression
Effector and Naturally Occurring Regulatory T Cells Display No Abnormalities in Activation Induced Cell Death in NOD Mice
BACKGROUND: Disturbed peripheral negative regulation might contribute to evolution of autoimmune insulitis in type 1 diabetes. This study evaluates the sensitivity of naïve/effector (Teff) and regulatory T cells (Treg) to activation-induced cell death mediated by Fas cross-linking in NOD and wild-type mice. PRINCIPAL FINDINGS: Both effector (CD25(-), FoxP3(-)) and suppressor (CD25(+), FoxP3(+)) CD4(+) T cells are negatively regulated by Fas cross-linking in mixed splenocyte populations of NOD, wild type mice and FoxP3-GFP trangeneess. Proliferation rates and sensitivity to Fas cross-linking are dissociated in Treg cells: fast cycling induced by IL-2 and CD3/CD28 stimulation improve Treg resistance to Fas-ligand (FasL) in both strains. The effector and suppressor CD4(+) subsets display balanced sensitivity to negative regulation under baseline conditions, IL-2 and CD3/CD28 stimulation, indicating that stimulation does not perturb immune homeostasis in NOD mice. Effective autocrine apoptosis of diabetogenic cells was evident from delayed onset and reduced incidence of adoptive disease transfer into NOD.SCID by CD4(+)CD25(-) T cells decorated with FasL protein. Treg resistant to Fas-mediated apoptosis retain suppressive activity in vitro. The only detectable differential response was reduced Teff proliferation and upregulation of CD25 following CD3-activation in NOD mice. CONCLUSION: These data document negative regulation of effector and suppressor cells by Fas cross-linking and dissociation between sensitivity to apoptosis and proliferation in stimulated Treg. There is no evidence that perturbed AICD in NOD mice initiates or promotes autoimmune insulitis
“A man’s gonna do what a man wants to do”: African American and Hispanic women’s perceptions about heterosexual relationships: a qualitative study
How employees perceive HRM practices: differences between public and private organizations
In recent years, there is a general consensus regarding the importance of Human Resource
Management (HRM) practices for the success or failure of organizations (Kehoe & Wright, 2013).
The contextual theory (Johns, 2006) argues that the contexts in which human activity take place–
nations, organizations, industries, and professions–are crucial, and have an impact on the nature of
that activity. In such cases, omnibus and discrete context can have an impact (Johns, 2006), and
workers might experience the same process differently in different contexts. Implementing HRM
best practices without taking into consideration various contexts (Jackson & Schuler, 1995), may
produce different and sometimes conflicting perspectives from those expected (Nishii, Lepak &
Schneider, 2008). Our objective is to determine if there are any differences in how employees
perceive HRM in public and private organizations, and to characterize the nature of those
differences if they exist.(undefined)info:eu-repo/semantics/publishedVersio
Group decision-making theories for child and family social work
There is increasing interest in decision making in social work. Much of the attention has been on individual professional judgement rather than on group decisions processes. This paper outlines key theoretical approaches from diverse fields of knowledge for conceptualising professional group decision processes in child and family social work, as a framework for future research and more focused theoretical developments. The main theoretical approaches considered include (1) group consensus processes; (2) exchange and the use of information; (3) naturalistic studies emphasising group complexity; and (4) incremental improvement processes. The analysis highlights the possible impact of individual, organisational and contextual factors, as well as their complex interconnections, on group decision making. The paper provides a valuable resource for reflecting on group decision processes in child and family social work, and how they complement individual professional judgements and the interactive processes with children and families. Next steps for the development of practice, policy, and research to improve group decision making are discussed. Using theoretical models to underpin empirical research will enable greater connection to be made between studies, and hence further the knowledge base for social work in this field
European Social Work Research Association SIG to Study Decisions, Assessment, and Risk
This is an Accepted Manuscript of an article published by Taylor & Francis Group in Journal of Evidence-Informed Social Work on 13/12/2017, available online:
http://www.tandfonline.com/doi/full/10.1080/23761407.2017.1394244
Purpose: The increasing interest in professional judgement and decision making is often separate from the discourse about “risk,” and the time-honored focus on assessment. Method: The need to develop research in and across these topics was recognized in the founding of a Decisions, Assessment, and Risk Special Interest Group (DARSIG) by the European Social Work Research Association in 2014. Results: The Group's interests include cognitive judgements; decision processes with clients, families, other professionals and courts; assessment tools and processes; the assessment, communication, and management of risk; and legal, ethical, and emotional aspects of these. This article outlines the founding and scope of DARSIG; gives an overview of decision making, assessment, and risk for practice; illustrates connections between these; and highlights future research directions. Discussion: Professional knowledge about decision making, assessment, and risk complements knowledge about effectiveness of interventions. Conclusion: DARSIG promises to be a useful mechanism for the purpose