Functional recognition of in vivo processed self antigen

C5, the fifth component of complement, Is a circulating self protein which induces complete tolerance in MHC class II restricted, CD4+ T cells due to the presentation of C5 taken up from plasma. Functional recognition of in vivo processed C5 was monitored by activation of C5 specific T cell hybrids cultured with antigen presenting cells (APC) from C5 expressing mice. Dendritic cells Isolated from various tissues (spleen, thymus, skin) proved to be the most efficient APC, since 10-to 50-fold more macrophages and at least 100- to 500-fold more B cells were needed to achieve similar T cell activation. Stimulatory C5 peptide - class II complexes generated in vivo were retained on the surface of dendritic cells but not on macrophages and B cells upon prolonged culture: Dendritic cells but not macrophages from thymus presented in vivo processed C5. Taken together these findings emphasize the crucial role dendritic cells play for recognition of soluble self proteins by MHC class II restricted T cell

Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells

The aryl hydrocarbon receptor (AHR)controls interleukin 22 production by T helper 17 cells (Th17). IL-22contributes to intestinalhomeostasis but has also been implicated inchronic inflammatory disorders and colorectal cancer, highlighting the need for appropriate regulation of IL-22 production. Upon activation, the AHR induces expression of cytochrome P4501 (CYP1) enzymes that in turn play an important feedback role that curtails the duration of AHR signaling by metabolizingAHRligands. Recently we described how agents that inhibit CYP1 function potentiate AHR signalingby disruptingmetabolic clearance of the endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). In the present study, we investigated the immune-modulating effects of environmental pollutants such as polycyclic aromatic hydrocarbons on Th17 differentiation and IL-22 production. Using Th17 cells deficient in CYP1 enzymes (Cyp1a1/1a2/1b1-/-)we show that these chemicals potentiate AHR activation through inhibition of CYP1 enzymes which leads to increases in intracellular AHR agonists. Our findings demonstrate that IL-22 production by Th17 cellsis profoundly enhanced by impaired CYP1-function and strongly suggest that chemicals able to modify CYP1 function or expression may disrupt AHR-mediated immune regulation by altering the levels of endogenous AHR agonist(s)

The Physics Case for the New Muon (g-2) Experiment

This White Paper briefly reviews the present status of the muon (g-2) experiment and the physics motivation for a new effort. The present comparison between experiment and theory indicates a tantalizing $3.4 \sigma$ deviation. An improvement in precision on this comparison by a factor of 2--with the central value remaining unchanged--will exceed the ``discovery'' threshold, with a sensitivity above $6 \sigma$. The 2.5-fold reduction improvement goal of the new Brookhaven E969 experiment, along with continued steady reduction of the standard model theory uncertainty, will achieve this more definitive test. Already, the (g-2) result is arguably the most compelling indicator of physics beyond the standard model and, at the very least, it represents a major constraint for speculative new theories such as supersymmetry or extra dimensions. In this report, we summarize the present experimental status and provide an up-to-date accounting of the standard model theory, including the expectations for improvement in the hadronic contributions, which dominate the overall uncertainty. Our primary focus is on the physics case that motivates improved experimental and theoretical efforts. Accordingly, we give examples of specific new-physics implications in the context of direct searches at the LHC as well as general arguments about the role of an improved (g-2) measurement. A brief summary of the plans for an upgraded effort complete the report.Comment: 18 pages, 7 figure

A diagrammatic treatment of neutrino oscillations

We present a covariant wave-packet approach to neutrino flavor transitions in vacuum. The approach is based on the technique of macroscopic Feynman diagrams describing the lepton number violating processes of production and absorption of virtual massive neutrinos at the macroscopically separated space-time regions ("source" and "detector"). Accordingly, the flavor transitions are a result of interference of the diagrams with neutrinos of different masses in the intermediate states. The statistically averaged probability of the process is representable as a multidimensional integral of the product of the factors which describe the differential flux density of massless neutrinos from the source, differential cross section of the neutrino interaction with the detector and a dimensionless factor responsible for the flavor transition. The conditions are analyzed under which the last factor can be treated as the flavor transition probability in the usual quantum-mechanical sense.Comment: 27 pages,7 figures, iopart class. Includes minor corrections made in proofs. References update

Neutrino oscillations and the effect of the finite lifetime of the neutrino source

We consider a neutrino source at rest and discuss a condition for the existence of neutrino oscillations which derives from the finite lifetime $\tau_S$ of the neutrino source particle. This condition is present if the neutrino source is a free particle such that its wave function is non-stationary. For a Gaussian wave function and with some simplifying assumptions, we study the modification of the usual oscillation probability stemming from $\tau_S$. In the present accelerator experiments the effect of $\tau_S$ can be neglected. We discuss some experimental situations where the source lifetime becomes relevant in the oscillation formula.Comment: 13 pages latex file with 2 figure

Effects of neutrino oscillations and neutrino magnetic moments on elastic neutrino-electron scattering

We consider elastic antineutrino-electron scattering taking into account possible effects of neutrino masses and mixing and of neutrino magnetic moments and electric dipole moments. Having in mind antineutrinos produced in a nuclear reactor we compute, in particular, the weak-electromagnetic interference terms which are linear in the magnetic (electric dipole) moments and also in the neutrino masses. We show that these terms are, however, suppressed compared to the pure weak and electromagnetic cross section. We also comment upon the possibility of using the electromagnetic cross section to investigate neutrino oscillations.Comment: 12 pages, REVTEX file, no figures, submitted to Phys.Rev.

Activation of the Aryl Hydrocarbon Receptor Interferes with Early Embryonic Development.

The transcriptional program of early embryonic development is tightly regulated by a set of well-defined transcription factors that suppress premature expression of differentiation genes and sustain the pluripotent identity. It is generally accepted that this program can be perturbed by environmental factors such as chemical pollutants; however, the precise molecular mechanisms remain unknown. The aryl hydrocarbon receptor (AHR) is a widely expressed nuclear receptor that senses environmental stimuli and modulates target gene expression. Here, we have investigated the AHR interactome in embryonic stem cells by mass spectrometry and show that ectopic activation of AHR during early differentiation disrupts the differentiation program via the chromatin remodeling complex NuRD (nucleosome remodeling and deacetylation). The activated AHR/NuRD complex altered the expression of differentiation-specific genes that control the first two developmental decisions without affecting the pluripotency program. These findings identify a mechanism that allows environmental stimuli to disrupt embryonic development through AHR signaling

Real Oscillations of Virtual Neutrinos

We study the conditions for neutrino oscillations in a field theoretical approach by taking into account that only the neutrino production and detection processes, which are localized in space around the coordinates $\vec{x}_P$ and $\vec{x}_D$, respectively, can be manipulated. In this sense the neutrinos whose oscillations are investigated appear as virtual lines connecting production with detection in the total Feynman graph and all neutrino fields or states to be found in the discussion are mass eigenfields or eigenstates. We perform a thorough examination of the integral over the spatial components of the inner neutrino momentum and show that in the asymptotic limit $L=|\vec{x}_D - \vec{x}_P| \rightarrow \infty$ the virtual neutrinos become ``real'' and under certain conditions the usual picture of neutrino oscillations emerges without ambiguities.Comment: 12 pages, pure LaTeX file, no figure

Characterising the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5

The implication of complement in multiple diseases over the last twenty years has fuelled interest in developing anti‐complement drugs. To date, the focus has been on C5; blocking cleavage of C5 prevents formation of two pro‐inflammatory activities, C5a anaphylatoxin and membrane attack complex. The concept of C5 blockade to inhibit inflammation dates back thirty years to the description of BB5.1, an anti‐C5 blocking monoclonal antibody raised in C5‐deficient mice. This antibody proved an invaluable tool to demonstrate complement involvement in mouse disease models and catalysed enthusiasm for anti‐complement drug development, culminating in the anti‐human C5 monoclonal antibody ecuizumab, the most successful anti‐complement drug to date, already in the clinic for several rare diseases. Despite its key role in providing proof‐of‐concept for C5 blockade, the mechanism of BB5.1 inhibition remains poorly understood. Here we characterised BB5.1 cross‐species inhibition, C5 binding affinity and chain specificity. BB5.1 efficiently inhibited C5 in mouse serum but not in human or other rodent sera; it prevented C5 cleavage and C5a generation. BB5.1 bound the C5 α‐chain with high affinity and slow off‐rate. BB5.1 complementarity determining regions were obtained and docking algorithms used to predict the likely binding interface on mouse C5

Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice.

BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans. OBJECTIVES: The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression. METHODS: Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD (9 ng TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring. RESULTS: TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3. DISCUSSION: Exposure to 9 ng TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352