A study of nitrogen metabolism in a case presenting short paroxysms of fever of unknown origin

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Statistical mechanics of clonal expansion in lymphocyte networks modelled with slow and fast variables

We study the Langevin dynamics of the adaptive immune system, modelled by a lymphocyte network in which the B cells are interacting with the T cells and antigen. We assume that B clones and T clones are evolving in different thermal noise environments and on different timescales. We derive stationary distributions and use statistical mechanics to study clonal expansion of B clones in this model when the B and T clone sizes are assumed to be the slow and fast variables respectively and vice versa. We derive distributions of B clone sizes and use general properties of ferromagnetic systems to predict characteristics of these distributions, such as the average B cell concentration, in some regimes where T cells can be modelled as binary variables. This analysis is independent of network topologies and its results are qualitatively consistent with experimental observations. In order to obtain full distributions we assume that the network topologies are random and locally equivalent to trees. The latter allows us to employ the Bethe-Peierls approach and to develop a theoretical framework which can be used to predict the distributions of B clone sizes. As an example we use this theory to compute distributions for the models of immune system defined on random regular networks.Comment: A more recent version (accepted for publication in Journal of Physics A: Mathematical and Theoretical) with improved figures, references, et

Temporally consistent species differences in parasite infection but no evidence for rapid parasite-mediated speciation in Lake Victoria cichlid fish

Abstract Parasites may have strong eco-evolutionary interactions with their hosts. Consequently, they may contribute to host diversification. The radiation of cichlid fish in Lake Victoria provides a good model to study the role of parasites in the early stages of speciation. We investigated patterns of macroparasite infection in a community of 17 sympatric cichlids from a recent radiation and 2 older species from 2 non-radiating lineages, to explore the opportunity for parasite-mediated speciation. Host species had different parasite infection profiles, which were only partially explained by ecological factors (diet, water depth). This may indicate that differences in infection are not simply the result of differences in exposure, but that hosts evolved species-specific resistance, consistent with parasite-mediated divergent selection. Infection was similar between sampling years, indicating that the direction of parasite-mediated selection is stable through time. We morphologically identified 6 Cichlidogyrus species, a gill parasite that is considered a good candidate for driving parasite-mediated speciation, because it is host species-specific and has radiated elsewhere in Africa. Species composition of Cichlidogyrus infection was similar among the most closely related host species (members of the Lake Victoria radiation), but two more distantly related species (belonging to non-radiating sister lineages) showed distinct infection profiles. This is inconsistent with a role for Cichlidogyrus in the early stages of divergence. To conclude, we find significant interspecific variation in parasite infection profiles, which is temporally consistent. We found no evidence that Cichlidogyrus-mediated selection contributes to the early stages of speciation. Instead, our findings indicate that species differences in infection accumulate after speciation.Peer reviewe

Phage Display in the Quest for New Selective Recognition Elements for Biosensors

Phages are bacterial viruses that have gained a significant role in biotechnology owing to their widely studied biology and many advantageous characteristics. Perhaps the best-known application of phages is phage display that refers to the expression of foreign peptides or proteins outside the phage virion as a fusion with one of the phage coat proteins. In 2018, one half of the Nobel prize in chemistry was awarded jointly to George P. Smith and Sir Gregory P. Winter "for the phage display of peptides and antibodies." The outstanding technology has evolved and developed considerably since its first description in 1985, and today phage display is commonly used in a wide variety of disciplines, including drug discovery, enzyme optimization, biomolecular interaction studies, as well as biosensor development. A cornerstone of all biosensors, regardless of the sensor platform or transduction scheme used, is a sensitive and selective bioreceptor, or a recognition element, that can provide specific binding to the target analyte. Many environmentally or pharmacologically interesting target analytes might not have naturally appropriate binding partners for biosensor development, but phage display can facilitate the production of novel receptors beyond known biomolecular interactions, or against toxic or nonimmunogenic targets, making the technology a valuable tool in the quest of new recognition elements for biosensor development.This study was supported by the Ministry of Economy and Competitiveness (Ministerio de Ciencia, Innovación y Universidades RTI2018-096410-B-C21). R.P. acknowledges UCM for a predoctoral grant and R.B. the PI17CIII/00045 grant from the AES-ISCIII program.S

Immunological changes in nestlings growing under predation risk

Predation is one of the most relevant selective forces in nature. However, the physiological mechanisms behind anti-predator strategies have been overlooked, despite their importance to understand predator-prey interactions. In this context, the immune system could be especially revealing due to its relationship with other critical functions and its ability to enhance prey's probabilities of survival to a predator's attack. Developing organisms (e.g. nestlings) are excellent models to study this topic because they suffer a high predation pressure while undergoing the majority of their development, which maximizes potential trade-offs between immunity and other biological functions. Using common blackbirds Turdus merula as model species, we experimentally investigated whether an elevated nest predation risk during the nestling period affects nestlings' immunity and its possible interactions with developmental conditions (i.e. body condition and growth). Experimental nestlings modified some components of their immunity, but only when considering body condition and growth rate, indicating a multifaceted immunological response to predation risk and an important mediator role of nestlings' developmental conditions. Predation risk induced a suppression of IgY but an increase in lymphocytes in nestlings with poor body condition. In addition, experimental but not control nestlings showed a negative correlation between growth and heterophils, demonstrating that nest predation risk can affect the interaction between growth and immunity. This study highlights the importance of immunity in anti-predator response in nestlings and shows the relevance of including physiological components to the study of predation risk.</p

Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease

Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis

BACKGROUND: Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen. METHODS: 27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins. RESULTS: mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season. CONCLUSION: The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation