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Past studies have revealed a dizzying array of coping techniques employed by persons living with inflammatory bowel disease (IBD). Unfortunately, research has provided little insight into when and why individuals adopt or abandon particular coping strategies. Using a retrospective narrative approach, we explored how participants made sense of changes in their approach to coping over time. Shifts in coping strategies were associated with particular illness experiences that wrought new understandings of IBD and novel identity challenges. They followed a common processual form and were marked by a movement away from techniques of purification, normalization, and banalization toward the development of a more communicative body. This was accompanied by notable shifts in identity work. Notably, participants moved from a preoccupation with maintaining continuity and sameness to permitting their extraordinary bodies to occupy a place in their public and personal identities. Implications of this process for theory and practice are discussed. [ABSTRACT FROM AUTHOR]

Few studies have addressed the experiences and meaning of family formation among adults who have experienced childhood maltreatment. From a critical interpretivist approach, we explored women's and men's perceptions of the risk of intergenerational transmission of family dysfunction in their stories of reproductive decisions. In this qualitative study, transcripts from interviews with 15 adults who self-reported childhood physical abuse, emotional abuse, neglect, or exposure to family violence were coded, thematically analysed, and patterns of meaning interpreted. In their reflections on their childhood experiences and the meaning of family formation in the present, risk was constructed in three ways: seven women who described themselves as meant to be mothers would not pass on dysfunction but rather a good family life; four women who described themselves as not meant to be mothers (voluntarily childless or parent allies) eliminated any risk of transmission of dysfunction; and two men and two women were uncertain about starting families and of their ability to eliminate the transfer of dysfunction. The findings offer an introduction to such adults' generative experiences, point to future research questions, and afford understanding for mental health professionals who can provide anticipatory guidance during the transition to parenthood for adults who have experienced childhood maltreatment. [ABSTRACT FROM AUTHOR]

Abstract: This experiment investigated a blood smear method as an alternative to flow cytometry for ploidy determination in Arctic charr, Salvelinus alpinus. Fertilized eggs were either treated with hydrostatic pressure (putative triploids) or untreated (diploid controls), and the embryos, alevins, and juveniles were then reared under identical conditions. Blood samples were collected from alevins (2 g average body weight) for blood smear analysis, and from juveniles (120 g average weight) for both blood smear analysis and flow cytometry. Student's t tests revealed significant (p < 0.0001) differences in mean erythrocyte length between the two groups, with pressure‐treated fish having higher values than the control group as alevins (20.43 ± 0.53 μm and 15.90 ± 0.45 μm respectively) and juveniles (22.83 ± 0.66 μm and 17.68 ± 0.45 μm respectively). Ploidy assignment obtained with blood smear analysis perfectly matched results obtained with flow cytometry. The blood smear method is therefore a valid, simple, and less expensive alternative to flow cytometry for the assessment of ploidy level in Arctic charr. [ABSTRACT FROM AUTHOR]

Although researchers, service providers, and clients are determined to improve partnerships within disability services, a lack of partnership persists. Using our research as a case study, we reflect on three limitations of common research methods and social change techniques in this area. We suggest that typical approaches struggle to move beyond taken-for-granted ideas, common-sense solutions, and established ideology in the field of disability. Consequently, they often fail to reveal important barriers to collaboration, identify innovative solutions, or initiate meaningful improvements in partnership. We propose a new approach to partnership research and reform grounded in a pragmatic model of social change and argue that projects based on isolated or simplistic data, majority-rule decision-making, simple and efficient planning, and restricted inside perspectives (where storytelling is limited) must be complemented by observational studies, socio-cultural analyses, and critical investigations. In short, we must understand why working relationships do not change to improve disability services. [ABSTRACT FROM AUTHOR]

Previous qualitative research findings have discussed motivations, decision-making, stigma, and resistance to pronatalism among voluntarily childless (VC) men and women. The current study placed such elements of the lifeworlds of VC individuals and dyads within the context of a life story of (re)making of the VC identity. Twelve life history and semistructured interviews with six VC men and women in three heterosexual couples in Canada were analyzed using thematic analysis. The VC choice was expressed as a decision to accept one's essential voluntary childlessness. The construction of the VC participants' bodies through their stories entailed episodes of conflict and resistance central to gendered experiences. We propose that this pattern of themes, in a pronatalist sociocultural context, points to a remaking of the figure of an extraordinary person from childhood, through to their current partnership, and into the future. These findings have implications for practitioners working with VC couples as they construct their identities, partnerships, reproductive decisions, life trajectories, and life projects. [ABSTRACT FROM AUTHOR]

A large body of literature explores historical trauma or intergenerational trauma among Aboriginal communities around the globe. This literature connects contemporary forms of social suffering and health inequity to broader historical processes of colonization and the residential school systems in Canada. There are tendencies within this literature, however, to focus on individual pathology and victimization while minimizing notions of resilience or well-being. Through a social constructionist lens, this research examined how interpersonal responses to historical traumas can be intertwined with moments of and strategies for resilience. Detailed narrative interviews occurred with four Aboriginal Cree elders living in central Saskatchewan, Canada, who all experienced historical trauma to some extent. From this analysis, we argue that health research among Aboriginal populations must be sensitive to the complex individual and social realities that necessarily involve both processes of historical and contemporary traumas as well as resilience, strength, and well-being. [ABSTRACT FROM AUTHOR]

The article responds to the article "Renunciation as Pedagogy" by Vanessa R. Sasson in the same issue. Topics include the role of grades and grading in higher education, the social and economic conditions of college students, and the roles of feedback and editing in university and college classes. College student motivation is addressed in relation to learning.

For approximately 150 years, Baha'is in Iran have been persecuted on the basis of their religion. Limitations to aspects of their lives have compelled them to face 'civic death' or migrate to other countries. This qualitative pilot study explored the experience of forced migration and how religion attenuates the disruption to the lives of Iranian Baha'is. Adaptive strategies that four participants utilised to re-establish continuity were examined. Participants who were satisfied with their lives developed a way to allow parallel cultural traditions (Iranian and Canadian) to co-exist; those who could not integrate found it difficult to maintain a balance between these traditions. [ABSTRACT FROM AUTHOR]

This paper offers a framework for redesigning Religious Studies doctoral programs so as to include a stream that prepares students to be teachers. The example used is the Canadian Laurier–Waterloo Ph.D. program. Carefully configured teacher training need not extend the length of a program, and it will prepare students to take up teaching and other positions both inside and outside universities and colleges. Introducing teacher training within a doctoral program will require some additional university resources, but will especially require rethinking the priorities of graduate education in the early 21st century. [ABSTRACT FROM PUBLISHER]

Phagocytosis, the process by which cells engulf large particles, requires a substantial contribution of membranes. Recent studies have revealed that intracellular compartments, including endocytic organelles and the endoplasmic reticulum (ER), can engage in fusion events with the plasma membrane at the sites of nascent phagosomes. The finding that ER proteins are delivered to phagosomes, where degraded peptides are loaded onto major histocompatibility complex (MHC) class II molecules, has significantly enhanced our understanding of the immune functions associated with these organelles. Although it is well known that pathogens are killed in phagosomes, the contribution of ER proteins to phagosomes has provided a novel pathway for the loading of exogenous peptides onto MHC class I molecules, a process known as cross-presentation. Thus, phagocytosis has evolved from a nutritional function in unicellular organisms to play key roles in both innate and adaptive immunity in vertebrates. [ABSTRACT FROM AUTHOR]

Phagocytosis, the process by which cells internalize large particulate materials from their milieu and sequester them in phagosomes, plays a role in a variety of cell functions ranging from nutrition in ameba to innate and adaptive immunity in mammals. Recent findings revealed unexpected characteristics of phagosomes, highlighting how this complex organelle may have evolved, from Dictyostelium to human, to become a key player in our ability to mount an efficient immune response against a variety of intracellular pathogens. [ABSTRACT FROM AUTHOR]

Pointing to parallels in the study of Jesus traditions and Pauline literature, but focusing explicitly on Gnosticism, it is argued that the Gestalt of ancient religions are often the result of ideological projections into the texts and the assumed religious traditions standing behind them by modern scholars. Dealing more appropriately with such a problematic phenomenon as Gnosticism, would entail reconsidering the conceptual categories employed in the description and interpretation of the phenomenon, as well as an object lesson in scholarly humility to avoid the hybris of colonising ancient texts and the communities who produced and valued them. [ABSTRACT FROM AUTHOR]

Acquisition of microbicidal properties by phagosomes requires the action of molecules which regulate the interactions between phagosomes and endocytic organelles. Members of the protein kinase C (PKC) superfamily of serine/threonine kinases are recruited to phagosomes with various kinetics during phagolysosome biogenesis. To study the role of PKC-α in this process, we compared the composition of latex bead-containing phagosomes isolated from control and dominant-negative (DN) PKC-α-overexpressing RAW 264.7 macrophages. Western blot analysis indicated that the levels of both lysosomal-associated membrane protein-1 and flotillin-1, which are acquired through interactions with late endosomes and lysosomes, are reduced in phagosomes from DN PKC-α-overexpressing macrophages. Proteomic characterization of latex bead-containing phagosomes revealed that recruitment of the small GTPase Rab7, cathepsin D, and cathepsin S is inhibited by DN PKC-α. Collectively, these data provide evidence that PKC-α plays a role in phagolysosome biogenesis, a critical process of the innate immune response against infections. [Copyright &y& Elsevier]

This article presents a particular teaching strategy that involves using food playfully in the classroom in order to change the mood, generate different forms of learning, and prod students to connect food and religion. I offer a rationale for teaching with food, then provide an application from a university course on Gnosticism. My goal is to encourage college and university teachers of religion to take food, and play, more seriously in their teaching. [ABSTRACT FROM AUTHOR]

Dimeric norspermidine and spermidine derivatives are strong competitive inhibitors of polyamine transport. A xylyl tether was used for the dimerization of various triamines and spermine via a secondary amino group, and of putrescine via an ether or an amino group. Dimerization of putrescine moieties potentiates their ability to compete against spermidine transport to a much greater extent than for triamine dimers. [Copyright &y& Elsevier]

Phagocytosis is the process that cells have evolved to internalise large particles such as mineral debris, which they store, or apoptotic cells and pathogens, which they have the capacity to kill and degrade. However, several important pathogens can suppress these killing functions and survive and multiply within phagosomes, causing disease. Recent advances in phagosome biology have been made possible largely by a model system that uses inert latex beads. The ability to purify latex bead-containing phagosomes has opened the door to allow comprehensive biochemical analyses and functional assays to study the molecular mechanisms governing phagosome function. These approaches have led to unique insights directly relevant for the understanding of the biology of intracellular pathogens and the ways by which they subvert their hosts. [Copyright &y& Elsevier]

Genomics and other high-throughput approaches, such as proteomics, are changing the way we study complex biological systems. In the past few years, these approaches have contributed markedly to improving our understanding of phagocytosis. Indeed, the ability to study biological systems by monitoring hundreds of proteins provides a level of resolution that is not attainable by the usual 'one protein at a time' approach. In this article, I discuss how proteomic approaches have revealed surprising findings that enable us to revisit established concepts, such as the origin of the phagosome membrane, and to propose new models of cell organization and the link between innate and adaptive immunity. [ABSTRACT FROM AUTHOR]

Focuses on the survival strategies of intracellular pathogens in the subversion of a young phagosome. Mechanisms and molecules involved in phagolysosome biogenesis; Kiss and run hypothesis; Subversion of phagolysosome biogenesis; Leishmania and its lipophosphoglycan.

Examines the relationship between the Golgi apparatus and the lysosome. Possible maintenance of lysosomes by transient fusion and fission processes with the compartment; Description of the protein targeting and transport in the cell.

Looks at enzymatic enantiogroup differentiation in meso compounds and its provisions of compounds with multiple stereogenic centers. Provision of a chiral building block; Further studies of the synthesis of natural products.

Antigen cross-presentation enables an efficient CD8+ T cell response against antigens from exogenous sources. In this issue of Immunity, identify lipid bodies as an unexpected new player involved in this complex cellular pathway. [Copyright &y& Elsevier]

Our understanding of the mechanisms by which peptides from proteins present in phagosomes and endosomes are processed and presented on MHC class I molecules, in a pathway called cross‐presentation, is still incomplete. One of the main questions arising from currently proposed models is how do proteins in the phagosome lumen reach the proteasome in the cytoplasm to be processed properly. In this issue of The EMBO Journal, Sengupta et al (2019) present evidence for a surprising turn of events where, in fact, the proteasome acts within the lumen of endosomes and phagosomes. [ABSTRACT FROM AUTHOR]

• The molecular mechanisms leading to the death of DN during PD are still unknown. • Inflammation and autoimmune mechanisms are likely to be involved in PD. • MitAP is the first mechanism linking PD to autoimmunity. • Several PD-related proteins are associated with mitochondria and lysosomes. Parkinson's disease (PD) is caused by the progressive loss of dopaminergic neurons and afflicts millions of people world-wide. The current treatments address only the late motor symptoms, with no cure or preventive therapeutic approaches. The contribution of dysfunctional immune mechanisms in PD has been clearly established, with an emphasis on neuroinflammation and microglial cell activation. Recent studies have widened the involvement of the immune system in this disease by clearly showing the engagement of adaptive immunity and antigen presentation processes, directly regulated by PD-related proteins, raising the question whether PD is an autoimmune disease. The contribution of autoimmune mechanisms in PD opens novel avenues for the development of preventive therapeutic approaches. [ABSTRACT FROM AUTHOR]

Despite common experiences of identity damage, decline, and deterioration, many brain injury survivors succeed in reconstructing robust identities in the wake of injury. Yet, while this accomplishment greatly benefits survivors' quality of life, little is known about how positive identity work might be facilitated or enhanced in therapeutic institutions. Drawing on data from a women's self-help group, we argue that an egalitarian, reflective, strength-focused, and gender-segregated environment can provide female ABI (acquired brain injury) survivors with a fertile scene for identity enhancement and offer unique opportunities for collective identity development. Sociolinguistic interactional analysis revealed four types of positive identity work undertaken within the group: constructing competent selves; tempering the threat of loss and impairment; resisting infantilisation and delegitimisation; and asserting a collective gender identity. This identity work was facilitated by specific programme attributes and activities and contributed to the global project of decentring disability and destigmatising impairments and losses. We call for increased attention to identity issues in brain injury rehabilitation and argue that gender-segregated programming can provide a unique space for female survivors to construct empowering individual and collective identities after injury. [ABSTRACT FROM AUTHOR]

The invariant chain (Ii) has pleiotropic functions and is a key factor in antigen presentation. Ii associates with major histocompatibility complex class II molecules in the endoplasmic reticulum (ER) and targets the complex in the endocytic pathway to allow antigenic peptide loading. The human Iip35 isoform includes a cytoplasmic extension containing a di-arginine motif causing ER retention. This minor isoform does not exist in mice and its function in humans has not been thoroughly investigated. We have recently generated transgenic mice expressing Iip35 and these were crossed with Ii-deficient mice to generate animals (Tgp35/mIiKO) expressing exclusively the human isoform. In these mice, we show that Iip35 is expressed in antigen presenting cells and is inducible by interferon gamma (IFN-γ). Despite the low constitutive expression of the protein and some minor differences in the Vβ repertoire of Tgp35/mIiKO mice, Iip35 restored thymic selection of CD4+ T cells and of invariant natural killer T cells. In vitro functional assays using purified primary macrophages treated with IFN-γ showed that Iip35 allows presentation of an Ii-dependent ovalbumin T-cell epitope. Altogether, our results suggest that Iip35 is functional and does not require co-expression of other isoforms for antigen presentation. [ABSTRACT FROM AUTHOR]

The classical view that endogenous antigens are processed by the proteasome and loaded on MHC class I molecules in the endoplasmic reticulum, while exogenous antigens taken up by endocytosis or phagocytosis are degraded and loaded on MHC class II in lysosome-derived organelles, has evolved along with the improvement of our understanding of the cell biology of antigen-presenting cells. In recent years, evidence for alternative presentation pathways has emerged. Exogenous antigens can be processed by the proteasome and loaded on MHC class I through a pathway called cross-presentation. Moreover, endogenous antigens can be targeted to lytic organelles for presentation on MHC class II through autophagy, a highly conserved cellular process of self-eating. Recent evidence indicates that the vacuolar degradation of endogenous antigens is also beneficial for presentation on MHC class I molecules. This review focuses on how various forms of autophagy participate to presentation of these antigens on MHC class I. [ABSTRACT FROM AUTHOR]

Isolated subcellular fractions have been instrumental in elucidating cell function. The use of such fractions for the identification and biochemical characterization of subcellular organelles, combined with cell- free systems, has provided key insights into the function and machineries of organelles, including those involved in vesicle transport, quality control and protein sorting. Despite their obvious utility, popular cell biology has come to regard in vitro-based approaches as inferior to in vivo-based approaches. Usual criticisms are contamination, non-representative processes and an inability to recreate the dynamic processes seen in vivo. In a similar way, proteomics has been viewed with reservation. Despite this, and building on the tradition of in vitro-based approaches, organelle proteomics based on liquid chromatography and tandem mass-spectrometry has recently made significant contributions to cell biology, and now allows the molecular machineries of organelles to be defined with high precision. [Copyright &y& Elsevier]

Abstract: A number of N-phenyl-N′-(2-chloroethyl)ureas (CEUs) have been shown to be potent antimitotics through their covalent binding to the colchicine-binding site on intracellular β-tubulin. The present communication aimed to evaluate the role of the electrophilic 2-chloroethyl amino moiety of CEU on cell growth inhibition and the specificity of the drugs as irreversible antagonists of the colchicine-binding site. To that end, several N-phenyl-N′-(2-ethyl)urea (EU), N-phenyl-N′-(2-chloroethyl)urea (CEU), N-aryl amino-2-oxazoline (OXA), and N-phenyl-N′-(2-chloroacetyl)urea (CAU) derivatives were prepared and tested for their antiproliferative activity, their effect on the cell cycle, and their irreversible binding to β-tubulin. EU derivatives were devoid of antiproliferative activity. CEUs (2h–2i, 2k, 2l, OXA 3e, 3h, 3i, 3k, 3l, tBCEU, and ICEU), OXA (3h, 3i, 3k, 3l, tBOXA, and IOXA), and CAU (4a–4m, tBCAU, and ICAU) had GI50 between 1.7 and 10μM on three tumor cell lines. Cytotoxic CEU and OXA arrested the cell cycle in G2/M phase, while the corresponding CAU were not phase specific. Finally, Western blot analysis clearly showed that only CEUs 2h, 2k, 2l, tBCEU, ICEU and OXA 3h, 3i, 3k, 3l, tBOXA ,and IOXA were able to bind irreversibly to the colchicine-binding site. Our results suggest that increasing the potency of the electrophilic moiety of the aromatic ureas enhances their antiproliferative activity but decreases significantly their capacity to covalently bind to the colchicine-binding site. [Copyright &y& Elsevier]

Abstract: In our ongoing research program aimed at the optimization of microtubule-self-assembly disrupting agents, we have prepared three series of phenylurea analogues (CEU), derived from N-(3-ω-hydroxyalkyl or 4-ω-hydroxyalkyl or 3-ω-hydroxyalkynyl)-phenyl-N′-(2-chloroethyl)ureas. Most compounds exhibit potent growth inhibitory activity on human colon carcinoma HT-29, human skin melanoma M21, and human breast carcinoma MCF-7 tumor cell lines, with a GI50 ranging from 250nM to 8μM. Among these new molecules, three CEUs exhibit GI50 in the nanomolar range. They are more potent by approximately an order of magnitude than previously described CEU analogues. As such, they are attractive hit compounds for the development of potent new alkylating antitubulin drugs. [Copyright &y& Elsevier]

Describes the role of the small GTPase rab5 in the function of both endocytic and phagocytic organelles. Accounts on the stages of lysosome biogenesis; Identification several molecules involved in membrane interaction and fusion; Visualization of the morphology of endocytic organelles.

The nature of relationships between service providers and parents of children with disabilities influences the health and wellbeing of parents and ultimately the quality of life of their children. The aim of this study was to explore parents' perceptions of their partnerships with service providers. We explored what was and was not working within these service relationships and solicited ideas for improved partnerships and services. We employed a qualitative, participatory research approach and adapted the Reflexive Methodology of Analysis in Partnership developed by Boudreault and Kalubi (2006). Thematic analysis and critical interpretation of the statements created in two focus groups by eight parents of nine children with disabilities generated eight themes: system complexity; funding; communication; navigation and advocacy; education; segregation; emotional support; and connecting with parents. Parents described difficulties in mediating partnerships in an ineffective disability service system and proposed practical solutions to these problems. We suggest that the structure of the disability service system is the root of these problems and must be radically changed to realize true partnership and client-centered services. Implications from this study for policy and practice include transforming the structure of the system, streamlining the organization and location of service information and delivery, including parents on decision-making bodies, and creating spaces for mutual peer support for parents of children with disabilities. [ABSTRACT FROM AUTHOR]

Summary Antigen presentation is essential for establishing immune tolerance and for immune responses against infectious disease and cancer. Although antigen presentation can be mediated by autophagy, here we demonstrate a pathway for mitochondrial antigen presentation (MitAP) that relies on the generation and trafficking of mitochondrial-derived vesicles (MDVs) rather than on autophagy/mitophagy. We find that PINK1 and Parkin, two mitochondrial proteins linked to Parkinson’s disease (PD), actively inhibit MDV formation and MitAP. In absence of PINK1 or Parkin, inflammatory conditions trigger MitAP in immune cells, both in vitro and in vivo. MitAP and the formation of MDVs require Rab9 and Sorting nexin 9, whose recruitment to mitochondria is inhibited by Parkin. The identification of PINK1 and Parkin as suppressors of an immune-response-eliciting pathway provoked by inflammation suggests new insights into PD pathology. [ABSTRACT FROM AUTHOR]

Autophagy is a key degradative pathway coordinated by external cues, including starvation, oxidative stress, or pathogen detection. Rare are the molecules known to contribute mechanistically to the regulation of autophagy and expressed specifically in particular environmental contexts or in distinct cell types. Here, we unravel the role of RUN and FYVE domain-containing protein 4 (RUFY4) as a positive molecular regulator of macroautophagy in primary dendritic cells (DCs). We show that exposure to interleukin-4 (IL-4) during DC differentiation enhances autophagy flux through mTORCl regulation and RUFY4 induction, which in turn actively promote LC3 degradation, Syntaxin 17-positive autophagosome formation, and lysosome tethering. Enhanced autophagy boosts endogenous antigen presentation by MHCII and allows host control of Brucella abortus replication in IL-4-treated DCs and in RUFY4-expressing cells. RUFY4 is therefore the first molecule characterized to date that promotes autophagy and influences endosome dynamics in a subset of immune cells. [ABSTRACT FROM AUTHOR]

Macroautophagy is a cellular pathway that degrades intracellular pathogens and contributes to antigen presentation. Herpes simplex virus 1 (HSV-1) infection triggers both macroautophagy and an additional form of autophagy that uses the nuclear envelope as a source of membrane. The present study constitutes the first in-depth analysis of nuclear envelope-derived autophagy (NEDA). We established LC3a as a marker that allowed us to distinguish between NEDA and macroautophagy in both immuno-fluorescence and flow cytometry. NEDA was observed in many different cell types, indicating that it is a general response to HSV-1 infection. This autophagic pathway is known to depend on the viral protein γ34.5, which can inhibit macroautophagy via binding to beclin-1. Using mutant viruses, we were able to show that binding of beclin-1 by γ 34.5 had no effect on NEDA, demonstrating that NEDA is regulated differently than macroautophagy. Instead, NEDA was triggered in response to γ34.5 binding to protein phosphatase lα, an interaction used by the virus to prevent host cells from shutting off protein translation. NEDA was not triggered when late viral protein production was inhibited with acyclovir or hippuristanol, indicating that the accumulation of these proteins might stress infected cells. Interestingly, expression of the late viral protein gH was sufficient to rescue NEDA in the context of infection with a virus that otherwise does not support strong late viral protein expression. We argue that NEDA is a cellular stress response triggered late during HSV-1 infection and might compensate for the viral alteration of the macroau-tophagic response. [ABSTRACT FROM AUTHOR]

Background: Senescent red blood cells (RBC) are recognized, phagocytosed and cleared by tissue macrophages. During this erythrophagocytosis (EP), RBC are engulfed and processed in special compartments called erythrophagosomes. We previously described that following EP, heme is rapidly degraded through the catabolic activity of heme oxygenase (HO). Extracted heme iron is then either exported or stored by macrophages. However, the cellular localization of the early steps of heme processing and iron extraction during EP remains to be clearly defined. Methodology/Principal Findings: We took advantage of our previously described cellular model of EP, using bone marrowderived macrophages (BMDM). The subcellular localization of both inducible and constitutive isoforms of HO (HO-1 and HO- 2), of the divalent metal transporters (Nramp1, Nramp2/DMT1, Fpn), and of the recently identified heme transporter HRG-1, was followed by fluorescence and electron microscopy during the earliest steps of EP. We also looked at some ER [calnexin, glucose-6-phosphatase (G6Pase) activity] and lysosomes (Lamp1) markers during EP. In both quiescent and LPS-activated BMDM, Nramp1 and Lamp1 were shown to be strong markers of the erythrophagolysosomal membrane. HRG-1 was also recruited to the erythrophagosome. Furthermore, we observed calnexin labeling and G6Pase activity at the erythrophagosomal membrane, indicating the contribution of ER in this phagocytosis model. In contrast, Nramp2/DMT1, Fpn, HO-1 and HO-2 were not detected at the membrane of erythrophagosomes. Conclusions/Significance: Our study highlights the subcellular localization of various heme- and iron-related proteins during early steps of EP, thereby suggesting a model for heme catabolism occurring outside the phagosome, with heme likely being transported into the cytosol through HRG1. The precise function of Nramp1 at the phagosomal membrane in this model remains to be determined. [ABSTRACT FROM AUTHOR]

Amoeba use phagocytosis to internalize bacteria as a source of nutrients, whereas multicellular organisms utilize this process as a defense mechanism to kill microbes and, in vertebrates, initiate a sustained immune response. By using a large‐scale approach to identify and compare the proteome and phosphoproteome of phagosomes isolated from distant organisms, and by comparative analysis over 39 taxa, we identified an ‘ancient’ core of phagosomal proteins around which the immune functions of this organelle have likely organized. Our data indicate that a larger proportion of the phagosome proteome, compared with the whole cell proteome, has been acquired through gene duplication at a period coinciding with the emergence of innate and adaptive immunity. Our study also characterizes in detail the acquisition of novel proteins and the significant remodeling of the phagosome phosphoproteome that contributed to modify the core constituents of this organelle in evolution. Our work thus provides the first thorough analysis of the changes that enabled the transformation of the phagosome from a phagotrophic compartment into an organelle fully competent for antigen presentation. [ABSTRACT FROM AUTHOR]

Summary: The ability of macrophages to clear pathogens and elicit a sustained immune response is regulated by various cytokines, including interferon-γ (IFN-γ). To investigate the molecular mechanisms by which IFN-γ modulates phagosome functions, we profiled the changes in composition, abundance, and phosphorylation of phagosome proteins in resting and activated macrophages by using quantitative proteomics and bioinformatics approaches. We identified 2415 phagosome proteins together with 2975 unique phosphorylation sites with a high level of sensitivity. Using network analyses, we determined that IFN-γ delays phagosomal acquisition of lysosomal hydrolases and peptidases for the gain of antigen presentation. Furthermore, this gain in antigen presentation is dependent on phagosomal networks of the actin cytoskeleton and vesicle-trafficking proteins, as well as Src kinases and calpain proteases. Major histocompatibility complex class I antigen-presentation assays validated the molecular participation of these networks in the enhanced capacity of IFN-γ-activated macrophages to crosspresent exogenous antigens to CD8+ T cells. [Copyright &y& Elsevier]

Viral proteins are usually processed by the 'classical' major histocompatibility complex (MHC) class I presentation pathway. Here we showed that although macrophages infected with herpes simplex virus type 1 (HSV-1) initially stimulated CD8+ T cells by this pathway, a second pathway involving a vacuolar compartment was triggered later during infection. Morphological and functional analyses indicated that distinct forms of autophagy facilitated the presentation of HSV-1 antigens on MHC class I molecules. One form of autophagy involved a previously unknown type of autophagosome that originated from the nuclear envelope. Whereas interferon-γ stimulated classical MHC class I presentation, fever-like hyperthermia and the pyrogenic cytokine interleukin 1β activated autophagy and the vacuolar processing of viral peptides. Viral peptides in autophagosomes were further processed by the proteasome, which suggests a complex interaction between the vacuolar and MHC class I presentation pathways. [ABSTRACT FROM AUTHOR]

The article presents abstracts on topics related to the science of religion which include the didactics of the study of religion, the conceptual as well as the methodological problems which interfere the accurate identification and measurement of religious mobilization in global civil society, and the possible cognitive factors that influence the cross-cultural incidence of spirit possession concepts.

Abstract: Aryl chloroethylureas (CEUs) are potent anti-neoplastic agents alkylating specific intracellular proteins such as βII-tubulin. Recently we have identified a new subset of CEU derived from compound 36 that alkylates thioredoxin isoform 1 (Trx-1), inhibits the nuclear translocation of Trx-1, and favors the accumulation of cells in G0/G1 phase. We have evaluated the effects of various substituents and their position on the aromatic ring of a series of derivatives of 36 on (i) the anti-proliferative activity, (ii) the cell cycle progression, (iii) the nuclear translocation of Trx-1, and (iv) their covalent binding to β-tubulin. The same experiments were performed on representative CEU derivatives where the 2-chloroethyl amino moiety is replaced by either an ethyl, a 2-aminooxazolinyl or a 2-chloroacetyl group. On one hand, our results suggest that CEUs substituted on the phenyl ring at position 3 or 4 by cycloalkyl and substituted cycloalkyl or cycloalkoxy groups inhibit the nuclear translocation of Trx-1 and arrest the cell cycle progression in G0/G1. On the other hand, CEUs substituted by a fused aromatic ring, an aliphatic chain, or a fused aliphatic ring are alkylating βII-tubulin but not Trx-1. Beside the expected inactivity of the ethylurea derivatives, none of the modification to the electrophilic moiety led to cross-selectivity of the drugs toward β-tubulin but increased the anti-proliferative activity and resulted in mitigated effects on Trx-1 translocation. [Copyright &y& Elsevier]

Inoculation of Leishmania ( L.) spp. promastigotes in the dermis of mammals by blood-feeding sand flies can be accompanied by the rapid recruitment of neutrophils, inflammatory monocytes and dendritic cells. Despite the presence of these lytic leucocytes, parasitism is efficiently established. We show here that Leishmania donovani promastigotes are targeted to two different compartments in neutrophils. The compartments harbouring either damaged or non-damaged parasites were characterized at the electron microscopy (EM) level using the glucose 6-phosphatase cytochemistry and endosome–phagosome fusion assays. One involves the contribution of lysosomes leading to the formation of highly lytic compartments where parasites are rapidly degraded. The other is lysosome-independent and involves the contribution of a compartment displaying some features of the endoplasmic reticulum (ER) where parasites are protected from degradation. Using genetically modified parasites, we show that the promastigote surface lipophosphoglycan (LPG) is required to inhibit lysosome fusion and maintain parasites in neutrophil compartments displaying ER features. L. donovani-harbouring neutrophils that eventually enter apoptosis can be phagocytosed by macrophages enabling the stealth entry of parasites into their final replicative host cells. Thus, the ability of L. donovani to avoid trafficking into lysosomes-derived compartments in short-lived neutrophils constitutes a key process for the subsequent establishment of long-term parasitism. [ABSTRACT FROM AUTHOR]

Abstract: Tubulin is the target of many anticancer drugs, including N-phenyl-N′-(2-chloroethyl)urea (CEU). Unlike most anti-β-tubulin agents, CEUs are protein monoalkylating agents binding through their N′-(2-chloroethyl)urea moiety to an amino acid nearby the colchicine-binding site on β-tubulin isoform-2. Following the previously synthesized and attractive N-(3-ω-hydroxyalkylphenyl)-N′-(2-chloroethyl)urea that exhibited growth inhibitory activity at the nanomolar level, we investigated the importance of lower alkyl and alkoxy groups to evaluate the effect of hydroxylated group and chain length on both cell growth inhibition and the mechanism of action of CEU. Here, we describe the preparation of two new series of CEU and show that the most potent CEU derivatives beside the ω-hydroxylated 1f were 2f and 3e, respectively. We have confirmed that the pentyl substituted CEUs 1f, 2f, and 3e are still covalently binding to β-tubulin and still arrest cell division in G2/M phase. [Copyright &y& Elsevier]