Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence

Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections.     

Consequences of polymorphism of 5'-GMP.Na2 in the vibrational spectra of metal complexes and isotopic derivatives

The commercial mononucleotides are frequently used to obtain metal complexes and isotopic derivatives. Normally, the spectra of these new compounds are compared with the spectra of the commercial mononucleotides. Nevertheless, important variations in the vibrational spectra of the disodium 5'-guanosine monophosphate, 5'-GMP, have been observed in this work produced by submitting the commercial salt to the same general laboratory process that the obtained compounds, i.e., solving the commercial salt in water and subsequent recrystallization. These changes have been analyzed and interpreted. The variations are not significant in disodium 5'-cytosine monophosphate, 5'-CMP. It is important to take this information into account before carrying out vibrational studies with this type of molecules, since some bands attributed to isotopic substitutions or to the metal attack may be a result of manipulation of the nucleotide (solving and recrystallization) instead of the studied effect. Thus, before any work in which the nucleotide salt is manipulated (deuteration, synthesis of other isotopic derivatives or metal-nucleotide complexes), it should be noted that the process to which the sample is submitted on its own is enough to modify the vibrational spectrum. Then, attention should be paid to the changes observed in the vibrational spectra of recrystallized mononucleotides, since recrystallization may lead to a considerable phase change, and this can notably alter the vibrational spectra.     

In vitro proliferation of blood,spleen and thymus leukocytes from the turtle Mauremys caspica

Cell-mediated immune responses is commonly evaluated by cell proliferation assays. Mitogens are known to induce a vigorous proliferative response in lymphoid cells from mammals but relatively fewer studies have investigated mitogen-mediated lymphoproliferation in non-mammalian animals. In the present work, we incubated spleen, thymus and blood leukocytes with phytohaemagglutinin (PHA), concanavalin A (Con A), lipopolysaccharide (LPS) and pokeweed mitogen (PWM), by different times of incubation (96 and 120 h) and at different concentrations. Our results show that the optimal mitogen concentrations inducing proliferation on leukocytes from Mauremys caspica were 20 microg/ml PHA, 1 microg/ml Con A, 12.5 microg/ml LPS and 1/150 dilution PWM. The optimal time of incubation was dependent on the type of leukocytes (peripheral blood leukocytes, splenic leukocytes or thymic cells) and the mitogen utilized.     

Genetic parameters for lactation traits of milking ewes: protein content and composition,fat, somatic cells and individual laboratory cheese yield

The effects of some environmental variation factors and the genetic parameters for total milk traits (fat content, protein content, casein content, serum protein content, lactation mean of individual laboratory cheese yield (LILCY), lactation mean of somatic cell count (LSCC), and milk yield) were estimated from the records of 1 111 Churra ewes. Genetic parameters were estimated by multivariate REML. Heritability for fat content was low (0.10) as is usually found in the Churra breed. Heritabilities for protein content, casein content, serum protein content, LILCY, milk yield and somatic cell count were 0.31, 0.30, 0.22, 0.09, 0.26 and 0.11, respectively. The highest heritability estimates were for protein and casein contents. Casein content is not advisable as an alternative to protein content as a selection criterion for cheese yield improvement; it does not have any compelling advantages and its measurement is costly. Our results for LSCC indicated that efforts should focus on improving the level of management rather than selecting for somatic cells, in the actual conditions of the Churra breed.     

Chromatin configuration and epigenetic landscape at the sex chromosome bivalent during equine spermatogenesis

Pairing of the sex chromosomes during mammalian meiosis is characterized by the formation of a unique heterochromatin structure at the XY body. The mechanisms underlying the formation of this nuclear domain are reportedly highly conserved from marsupials to mammals. In this study, we demonstrate that in contrast to all eutherian species studied to date, partial synapsis of the heterologous sex chromosomes during pachytene stage in the horse is not associated with the formation of a typical macrochromatin domain at the XY body. While phosphorylated histone H2AX (γH2AX) and macroH2A1.2 are present as a diffuse signal over the entire macrochromatin domain in mouse pachytene spermatocytes, γH2AX, macroH2A1.2, and the cohesin subunit SMC3 are preferentially enriched at meiotic sex chromosome cores in equine spermatocytes. Moreover, although several histone modifications associated with this nuclear domain in the mouse such as H3K4me2 and ubH2A are conspicuously absent in the equine XY body, prominent RNA polymerase II foci persist at the sex chromosomes. Thus, the localization of key marker proteins and histone modifications associated with the XY body in the horse differs significantly from all other mammalian systems described. These results demonstrate that the epigenetic landscape and heterochromatinization of the equine XY body might be regulated by alternative mechanisms and that some features of XY body formation may be evolutionary divergent in the domestic horse. We propose equine spermatogenesis as a unique model system for the study of the regulatory networks leading to the epigenetic control of gene expression during XY body formation.     

Global self-organization of the cellular metabolic structure

Background

Over many years, it has been assumed that enzymes work either in an isolated way, or organized in small catalytic groups. Several studies performed using “metabolic networks models” are helping to understand the degree of functional complexity that characterizes enzymatic dynamic systems. In a previous work, we used “dissipative metabolic networks” (DMNs) to show that enzymes can present a self-organized global functional structure, in which several sets of enzymes are always in an active state, whereas the rest of molecular catalytic sets exhibit dynamics of on-off changing states. We suggested that this kind of global metabolic dynamics might be a genuine and universal functional configuration of the cellular metabolic structure, common to all living cells. Later, a different group has shown experimentally that this kind of functional structure does, indeed, exist in several microorganisms.

Methodology/Principal Findings

Here we have analyzed around 2.500.000 different DMNs in order to investigate the underlying mechanism of this dynamic global configuration. The numerical analyses that we have performed show that this global configuration is an emergent property inherent to the cellular metabolic dynamics. Concretely, we have found that the existence of a high number of enzymatic subsystems belonging to the DMNs is the fundamental element for the spontaneous emergence of a functional reactive structure characterized by a metabolic core formed by several sets of enzymes always in an active state.

Conclusions/Significance

This self-organized dynamic structure seems to be an intrinsic characteristic of metabolism, common to all living cellular organisms. To better understand cellular functionality, it will be crucial to structurally characterize these enzymatic self-organized global structures.     

The effects of tin (Sn) additions on the growth of spinach plants

An increase in bioavailable tin in the environment could result in bioaccumulation thereof in agricultural crops, and therefore, have adverse health consequences on humans that eat these crops. The aims of the current study were thus to assess the uptake of Sn by spinach plants, and the subsequent effects this will have on the uptake of Na, Zn, K, Ca, and Mg as well as the growth of spinach plants. Spinach plants were grown in sand culture and received tin at concentrations of 0.02, 0.2, 2 and 20 mg/L along with a nutrient solution. The uptake of tin at detectible concentrations only occurred at the highest concentrations (2 and 20 mg/L), and it was mostly retained in the roots of the plants. Tin additions also resulted in no visual toxicity symptoms, and might be beneficial to biomass production. Further field trials are needed to ensure that these experimental results remain true under field conditions.