Antigen presenting capacity of murine splenic myeloid cells

BACKGROUND: The spleen is an important site for hematopoiesis. It supports development of myeloid cells from bone marrow-derived precursors entering from blood. Myeloid subsets in spleen are not well characterised although dendritic cell (DC) subsets are clearly defined in terms of phenotype, development and functional role. Recently a novel dendritic-like cell type in spleen named ‘L-DC’ was distinguished from other known dendritic and myeloid cells by its distinct phenotype and developmental origin. That study also redefined splenic eosinophils as well as resident and inflammatory monocytes in spleen. RESULTS: L-DC are shown to be distinct from known splenic macrophages and monocyte subsets. Using a new flow cytometric procedure, it has been possible to identify and isolate L-DC in order to assess their functional competence and ability to activate T cells both in vivo and in vitro. L-DC are readily accessible to antigen given intravenously through receptor-mediated endocytosis. They are also capable of CD8(+) T cell activation through antigen cross presentation, with subsequent induction of cytotoxic effector T cells. L-DC are MHCII(−) cells and unable to activate CD4(+) T cells, a property which clearly distinguishes them from conventional DC. The myeloid subsets of resident monocytes, inflammatory monocytes, neutrophils and eosinophils, were found to have varying capacities to take up antigen, but were uniformly unable to activate either CD4(+) T cells or CD8(+) T cells. CONCLUSION: The results presented here demonstrate that L-DC in spleen are distinct from other myeloid cells in that they can process antigen for CD8(+) T cell activation and induction of cytotoxic effector function, while both L-DC and myeloid subsets remain unable to activate CD4(+) T cells. The L-DC subset in spleen is therefore distinct as an antigen presenting cell

Screening of cosmological constant in non-local cosmology

We consider a model of non-local gravity with a large bare cosmological constant, $\Lambda$, and study its cosmological solutions. The model is characterized by a function $f(\psi)=f_0 e^{\alpha\psi}$ where $\psi=\Box^{-1}R$ and $\alpha$ is a real dimensionless parameter. In the absence of matter, we find an expanding universe solution $a\propto t^n$ with $n<1$, that is, a universe with decelarated expansion without any fine-tuning of the parameter. Thus the effect of the cosmological constant is effectively shielded in this solution. It has been known that solutions in non-local gravity often suffer from the existence of ghost modes. In the present case we find the solution is ghost-free if $\alpha>\alpha_{cr}\approx0.17$. This is quite a weak condition. We argue that the solution is stable against the includion of matter fields. Thus our solution opens up new possibilities for solution to the cosmological constant problem.Comment: 7 pages, 1 figure, LaTeX, V2:Some clarifications and references adde

Solving the mystery of human sleep schedules one mutation at a time.

Sleep behavior remains one of the most enigmatic areas of life. The unanswered questions range from "why do we sleep?" to "how we can improve sleep in today's society?" Identification of mutations responsible for altered circadian regulation of human sleep lead to unique opportunities for probing these territories. In this review, we summarize causative circadian mutations found from familial genetic studies to date. We also describe how these mutations mechanistically affect circadian function and lead to altered sleep behaviors, including shifted or shortening of sleep patterns. In addition, we discuss how the investigation of mutations can not only expand our understanding of the molecular mechanisms regulating the circadian clock and sleep duration, but also bridge the pathways between clock/sleep and other human physiological conditions and ailments such as metabolic regulation and migraine headaches

Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability

Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability. Am J Physiol Renal Physiol 313: F174 –F183, 2017. First published March 29, 2017; doi:10.1152/ajprenal.00482.2016.—The goals of this study were to 1) develop a computational model of solute transport and oxygenation in the kidney of the female spontaneously hypertensive rat (SHR), and 2) apply that model to investigate sex differences in nitric oxide (NO) levels in SHR and their effects on medullary oxygenation and oxidative stress. To accomplish these goals, we first measured NO synthase (NOS) 1 and NOS3 protein expression levels in total renal microvessels of male and female SHR. We found that the expression of both NOS1 and NOS3 is higher in the renal vasculature of females compared with males. To predict the implications of that finding on medullary oxygenation and oxidative stress levels, we developed a detailed computational model of the female SHR kidney. The model was based on a published male kidney model and represents solute transport and the biochemical reactions among O2, NO, and superoxide (O2 ) in the renal medulla. Model simulations conducted using both male and female SHR kidney models predicted significant radial gradients in interstitial fluid oxygen tension (PO2) and NO and O2 concentration in the outer medulla and upper inner medulla. The models also predicted that increases in endothelial NO-generating capacity, even when limited to specific vascular segments, may substantially raise medullary NO and PO2 levels. Other potential sex differences in SHR, including O2 production rate, are predicted to significantly impact oxidative stress levels, but effects on NO concentration and PO2 are limited.This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-106102 to A. T. Layton, and by American Heart Association Grant 14GRNT20480199 to J. C. Sullivan. (R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases; 14GRNT20480199 - American Heart Association)Accepted manuscrip

Reciprocity in Social Networks with Capacity Constraints

Directed links -- representing asymmetric social ties or interactions (e.g., "follower-followee") -- arise naturally in many social networks and other complex networks, giving rise to directed graphs (or digraphs) as basic topological models for these networks. Reciprocity, defined for a digraph as the percentage of edges with a reciprocal edge, is a key metric that has been used in the literature to compare different directed networks and provide "hints" about their structural properties: for example, are reciprocal edges generated randomly by chance or are there other processes driving their generation? In this paper we study the problem of maximizing achievable reciprocity for an ensemble of digraphs with the same prescribed in- and out-degree sequences. We show that the maximum reciprocity hinges crucially on the in- and out-degree sequences, which may be intuitively interpreted as constraints on some "social capacities" of nodes and impose fundamental limits on achievable reciprocity. We show that it is NP-complete to decide the achievability of a simple upper bound on maximum reciprocity, and provide conditions for achieving it. We demonstrate that many real networks exhibit reciprocities surprisingly close to the upper bound, which implies that users in these social networks are in a sense more "social" than suggested by the empirical reciprocity alone in that they are more willing to reciprocate, subject to their "social capacity" constraints. We find some surprising linear relationships between empirical reciprocity and the bound. We also show that a particular type of small network motifs that we call 3-paths are the major source of loss in reciprocity for real networks