Mach's Principle and Model for a Broken Symmetric Theory of Gravity

We investigate spontaneous symmetry breaking in a conformally invariant gravitational model. In particular, we use a conformally invariant scalar tensor theory as the vacuum sector of a gravitational model to examine the idea that gravitational coupling may be the result of a spontaneous symmetry breaking. In this model matter is taken to be coupled with a metric which is different but conformally related to the metric appearing explicitly in the vacuum sector. We show that after the spontaneous symmetry breaking the resulting theory is consistent with Mach's principle in the sense that inertial masses of particles have variable configurations in a cosmological context. Moreover, our analysis allows to construct a mechanism in which the resulting large vacuum energy density relaxes during evolution of the universe.Comment: 9 pages, no figure

Mass-Deformed BLG Theory in Light-Cone Superspace

Maximally supersymmetric mass deformation of the Bagger-Lambert-Gustavsson (BLG) theory corresponds to a {non-central} extension of the d=3 N=8 Poincare superalgebra (allowed in three dimensions). We obtain its light-cone superspace formulation which has a novel feature of the dynamical supersymmetry generators being {cubic} in the kinematical ones. The mass deformation picks a quaternionic direction, which breaks the SO(8) R-symmetry down to SO(4)xSO(4). The Hamiltonian of the theory is shown to be a quadratic form of the dynamical supersymmetry transformations, to all orders in the mass parameter, M, and the structure constants, f^{a b c d}.Comment: 23 page

Determinants of postnatal spleen tissue regeneration and organogenesis

Abstract The spleen is an organ that filters the blood and is responsible for generating blood-borne immune responses. It is also an organ with a remarkable capacity to regenerate. Techniques for splenic auto-transplantation have emerged to take advantage of this characteristic and rebuild spleen tissue in individuals undergoing splenectomy. While this procedure has been performed for decades, the underlying mechanisms controlling spleen regeneration have remained elusive. Insights into secondary lymphoid organogenesis and the roles of stromal organiser cells and lymphotoxin signalling in lymph node development have helped reveal similar requirements for spleen regeneration. These factors are now considered in the regulation of embryonic and postnatal spleen formation, and in the establishment of mature white pulp and marginal zone compartments which are essential for spleen-mediated immunity. A greater understanding of the cellular and molecular mechanisms which control spleen development will assist in the design of more precise and efficient tissue grafting methods for spleen regeneration on demand. Regeneration of organs which harbour functional white pulp tissue will also offer novel opportunities for effective immunotherapy against cancer as well as infectious diseases

Colonic Patch and colonic SILT development are independent and differentially-regulated events

Intestinal lymphoid tissues have to simultaneously ensure protection against pathogens and tolerance towards commensals. Despite such vital functions, their development in the colon is poorly understood. Here, we show that the two distinct lymphoid tissues of the colon–colonic patches and colonic SILTs–can easily be distinguished based on anatomical location, developmental timeframe and cellular organization. Furthermore, whereas colonic patch development depended on CXCL13-mediated LTi cell clustering followed by LTα-mediated consolidation, early LTi clustering at SILT anlagen did not require CXCL13, CCR6 or CXCR3. Subsequent dendritic cell recruitment to and gp38+VCAM-1+ lymphoid stromal cell differentiation within SILTs required LTα; B cell recruitment and follicular dendritic cell differentiation depended on MyD88-mediated signalling, but not the microflora. In conclusion, our data demonstrate that different mechanisms, mediated mainly by programmed stimuli, induce the formation of distinct colonic lymphoid tissues, therefore suggesting that these tissues may have different functions

Experimental stroke differentially affects discrete subpopulations of splenic macrophages

Changes to the immune system after stroke are complex and can result in both pro-inflammatory and immunosuppressive consequences. Following ischemic stroke, brain resident microglia are activated and circulating monocytes are recruited to the injury site. In contrast, there is a systemic deactivation of monocytes/macrophages that may contribute to immunosuppression and the high incidence of bacterial infection experienced by stroke patients. The manipulation of macrophage subsets may be a useful therapeutic strategy to reduce infection and improve outcome in patients after stroke. Recent research has enhanced our understanding of the heterogeneity of macrophages even within the same tissue. The spleen is the largest natural reservoir of immune cells, many of which are mobilized to the site of injury after ischemic stroke and is notable for the diversity of its functionally distinct macrophage subpopulations associated with specific micro-anatomical locations. Here, we describe the effects of experimental stroke in mice on these distinct splenic macrophage subpopulations. Red pulp (RP) and marginal zone macrophages (MZM) specifically showed increases in density and alterations in micro-anatomical location. These changes were not due to increased recruitment from the bone marrow but may be associated with increases in local proliferation. Genes associated with phagocytosis and proteolytic processing were upregulated in the spleen after stroke with increased expression of the lysosome-associated protein lysosomal-associated membrane proteins specifically increased in RP and MZM subsets. In contrast, MHC class II expression was reduced specifically in these populations. Furthermore, genes associated with macrophage ability to communicate with other immune cells, such as co-stimulatory molecules and inflammatory cytokine production, were also downregulated in the spleen after stroke. These findings suggest that selective splenic macrophage functions could be impaired after stroke and the contribution of macrophages to stroke-associated pathology and infectious complications should be considered at a subset-specific level. Therefore, optimal therapeutic manipulation of macrophages to improve stroke outcome is likely to require selective targeting of functionally and spatially distinct subpopulations

Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation

Canonical Wnt signaling has been implicated in various aspects of hematopoiesis. Its role is controversial due to different outcomes between various inducible Wnt-signaling loss-of-function models and also compared with gain-of-function systems. We therefore studied a mouse deficient for a Wnt gene that seemed to play a nonredundant role in hematopoiesis. Mice lacking Wnt3a die prenatally around embryonic day (E) 12.5, allowing fetal hematopoiesis to be studied using in vitro assays and transplantation into irradiated recipient mice. Here we show that Wnt3a deficiency leads to a reduction in the numbers of hematopoietic stem cells (HSCs) and progenitor cells in the fetal liver (FL) and to severely reduced reconstitution capacity as measured in secondary transplantation assays. This deficiency is irreversible and cannot be restored by transplantation into Wnt3a competent mice. The impaired long-term repopulation capacity of Wnt3a-/- HSCs could not be explained by altered cell cycle or survival of primitive progenitors. Moreover, Wnt3a deficiency affected myeloid but not B-lymphoid development at the progenitor level, and affected immature thymocyte differentiation. Our results show that Wnt3a signaling not only provides proliferative stimuli, such as for immature thymocytes, but also regulates cell fate decisions of HSC during hematopoiesis

Regulation of immunity during visceral Leishmania infection

Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis. The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world. Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes. However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response. These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response. We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host. A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease.The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement No.602773 (Project KINDRED). VR is supported by a post-doctoral fellowship granted by the KINDReD consortium. RS thanks the Foundation for Science and Technology (FCT) for an Investigator Grant (IF/00021/2014). This work was supported by grants to JE from ANR (LEISH-APO, France), Partenariat Hubert Curien (PHC) (program Volubilis, MA/11/262). JE acknowledges the support of the Canada Research Chair Program

In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria

Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.São Paulo Research Foundation grants: (2011/24038-1 [MRDL], 2009/08559-1 [HBdS], CAPES/IGC 04/ 2012 [MRDL, CET])

Time to full enteral feeding after necrotizing enterocolitis in preterm-born children is related to neurodevelopment at 2-3 years of age

BACKGROUND: Necrotizing enterocolitis (NEC) is associated with poorer neurodevelopment. It is, however, unclear which factors besides surgery affect neurodevelopment in preterm-born children surviving NEC. AIMS: We determined whether time to full enteral feeding (FEFt) and post-NEC complications after NEC were associated with neurodevelopment. STUDY DESIGN: Prospective observational cohort study. SUBJECTS: Two to three year old preterm-born children who survived NEC (Bells stage ≥ 2). We categorized children in two groups, one group shorter and equal and one group longer than the group's median FEFt. Post-NEC complications included recurrent NEC and/or post-NEC stricture. OUTCOME MEASURES: Bayley Scales of Infants and Toddler Development III (Bayley-III) and Child Behavior Checklist (CBCL). Associations between Bayley-III and CBCL scores with FEFt and Post-NEC complications were determined using linear regression analyses, adjusted for severity of illness and potential confounders. RESULTS: We included 44 children, median gestational age of 27.9 [IQR: 26.7-29.3] weeks, birth weight 1148 [IQR: 810-1461] grams. Median FEFt after NEC was 20 [IQR: 16-30] days. Median follow-up age was 25.7 [IQR: 24.8-33.5] months. FEFt > 20 days was associated with lower cognitive and lower motor composite scores of the Bayley-III (B: -8.6, 95% CI -16.7 to -0.4, and B: -9.0, 95% CI, -16.7 to -1.4). FEFt was not associated with CBCL scores. Post-NEC complications (n = 11) were not associated with Bayley-III scores nor with CBCL scores. CONCLUSIONS: Prolonged FEFt after NEC in preterm-born children surviving NEC is associated with lower cognitive and lower motor composite scores at the age of 2-3 years. These results show the importance of limiting the duration of the nil per mouth regimen if and when possible

A comparison of the early motor repertoire of very preterm infants and term infants

OBJECTIVE: To obtain reference data on the early motor repertoire of very preterm infants compared with healthy term infants at three months' post-term age. STUDY DESIGN: In this observational study, using Prechtl's method on the assessment of the early motor repertoire, we compared the quality of fidgety movements and the concurrent motor optimality score - revised of infants with a gestational age <30 weeks and/or a birth weight <1000 g with healthy infants with a gestational age of 37-42 weeks. RESULTS: One hundred eighty very preterm and 180 healthy term infants participated. The median motor optimality scores - revised of very preterm infants were significantly lower in comparison to those of term infants, with scores of 24 (25th-75th percentiles: 23-26) and 26 (25th-75th percentiles: 26-28), respectively. Fidgety movements were aberrant (abnormal or absent) more often in very preterm infants than in term infants. The odds ratio was 4.59 (95% CI, 1.51-13.92). Compared with term infants, very preterm infants had poorer scores on the subscales age-adequate movement repertoire, observed postural patterns, and movement character with odds ratios ≥2.97. We found no differences regarding observed movement patterns. CONCLUSION: This study provides reference data on the early motor repertoire of very preterm and healthy term infants. It demonstrates that the early motor repertoire of very preterm infants is poorer than that of term infants, a finding consistent with existing knowledge that prematurity increases the risk of poor neurodevelopment