DEP-domain-mediated regulation of GPCR signaling responses

G protein-coupled receptors (GPCRs) mediate cellular responses to a variety of stimuli, but how specific responses are regulated has been elusive, as the types of GPCRs vastly outnumber the classes of G protein heterotrimers available to initiate downstream signaling. In our analysis of signaling proteins containing DEP domains ( approximately 90 residue sequence motifs first recognized in fly Dishevelled, worm EGL-10, and mammalian Pleckstrin), we find that DEP domains are responsible for specific recognition of GPCRs. We examined the yeast regulator of G protein signaling (RGS) protein Sst2 and demonstrate that the DEP domains in Sst2 mediate binding to its cognate GPCR (Ste2). DEP-domain-mediated tethering promotes downregulation by placing the RGS protein in proximity to its substrate (receptor-activated Galpha subunit). Sst2 docks to the Ste2 cytosolic tail, but only its unphosphorylated state, allowing for release and recycling of this regulator upon receptor desensitization and internalization. DEP-domain-mediated targeting of effectors and regulators to specific GPCRs provides a means to dictate the nature, duration, and specificity of the response.     

Modeling systems-level regulation of host immune responses

Many pathogens are able to manipulate the signaling pathways responsible for the generation of host immune responses. Here we examine and model a respiratory infection system in which disruption of host immune functions or of bacterial factors changes the dynamics of the infection. We synthesize the network of interactions between host immune components and two closely related bacteria in the genus Bordetellae. We incorporate existing experimental information on the timing of immune regulatory events into a discrete dynamic model, and verify the model by comparing the effects of simulated disruptions to the experimental outcome of knockout mutations. Our model indicates that the infection time course of both Bordetellae can be separated into three distinct phases based on the most active immune processes. We compare and discuss the effect of the species-specific virulence factors on disrupting the immune response during their infection of naive, antibody-treated, diseased, or convalescent hosts. Our model offers predictions regarding cytokine regulation, key immune components, and clearance of secondary infections; we experimentally validate two of these predictions. This type of modeling provides new insights into the virulence, pathogenesis, and host adaptation of disease-causing microorganisms and allows systems-level analysis that is not always possible using traditional methods.     

Negative regulation of toll-like receptor-mediated immune responses

Toll-like receptors (TLRs) are involved in host defence against invading pathogens, functioning as primary sensors of microbial products and activating signalling pathways that induce the expression of immune and pro-inflammatory genes. However, TLRs have also been implicated in several immune-mediated and inflammatory diseases. As the immune system needs to constantly strike a balance between activation and inhibition to avoid detrimental and inappropriate inflammatory responses, TLR signalling must be tightly regulated. Here, we discuss the various negative regulatory mechanisms that have evolved to attenuate TLR signalling to maintain this immunological balance.     

Attention and regulation of EEG alpha-attenuation responses

Two experiments with 16 normal adults of both sexes tested the hypothesis that inattention to a biofeedback display is associated with increased variability of those physiological processes that had been regulated by the biofeedback. Each experiment was a repeated-measures-on-independent-subjects-design. Dependent variables were the time durations and the mean rms power of two mutually exclusive segments of the parietal-occipital EEG: alpha and not-alpha segments. Independent variables were combination of counting tasks and instructions to look at, listen to, and count visual and auditory flashes and clicks. The durations of alpha and not-alpha segments were controlled or regulated by means of an alpha-contingent visual feedback stimulus, Attention to the feedback stimulus was challenged by instructions to count other, noncontingent stimuli. Control of alpha and not-alpha segments was least for conditions of (1) “sham” feedback, and (2) feedback with instructions to count noncontingent auditory clicks, which were presented 3/sec while the feedback visual stimuli were occurring. A new EEG test of attention and distraction was suggested.     

Mitochondrial regulation of CRAC channel-driven cellular responses

One widespread and conserved Ca(2+) entry pathway in eukaryotic cells is the store-operated CRAC channel and Ca(2+) entry through these channels activates a disparate array of cellular responses. Under physiological conditions, mitochondria are important regulators of CRAC channel gating. Through these actions, mitochondria help control a range of spatially and temporally distinct CRAC channel-driven responses including enzyme activation, secretion, intercellular communication through paracrine signals and gene expression.     

Epigenetic regulation in plant abiotic stress responses

In eukaryotic cells, gene expression is greatly influenced by the dynamic chromatin environment. Epigenetic mechanisms, including covalent modifications to DNA and histone tails and the accessibility of chromatin, create various chromatin states for stress‐responsive gene expression that is important for adaptation to harsh environmental conditions. Recent studies have revealed that many epigenetic factors participate in abiotic stress responses, and various chromatin modifications are changed when plants are exposed to stressful environments. In this review, we summarize recent progress on the cross‐talk between abiotic stress response pathways and epigenetic regulatory pathways in plants. Our review focuses on epigenetic regulation of plant responses to extreme temperatures, drought, salinity, the stress hormone abscisic acid, nutrient limitations and ultraviolet stress, and on epigenetic mechanisms of stress memory.     

Idiotypic regulation of mouse anti-H-2 antibody responses

Mouse-immunoglobulin (MIg) tolerant rabbits immunized with mouse H-2 antibodies produced anti-idiotype antisera, which were reactive towards specific B- and T-cell receptors. One such rabbit antiserum (from rabbit 5936) defines a family of idiotypes (Id) designated 5936-idiotypes (Rubin et al. 1979). The present experiments were performed in order to establish (1) the nature of 5936-Id⁺ serum molecules, (2) the specificity of 5936-Id⁺ serum molecules, (3) the association of the 5936-Id genes to allotype and/orH-2 genes and (4) the immunological role of 5936-Id⁺ serum molecules. A sensitive, radioimmunoassay employing¹²⁵I-labelled-F(ab)₂ fragments of B6 anti-B10.BR MIg pool, 5936 antiserum, and a sheep anti-rabbit immunoglobulin antiserum, was used.—The results suggested that 5936-Id⁺ serum molecules were exclusively MIg, and that they were mainly of the IgG₁ class. Such molecules were induced in B6 mice (H-2 ^b /Ig-1 ^b ) upon immunization with H-2^k but not with H-2^q alloantigen or conventional antigens. The 5936-Id were found to be associated with Ig-1^b allotypes and theH-2 ^b complex may contain immune response (Ir) genes which, in comparison withIr genes inH-2 ^d andH-2 ^s , favor the expression of 5936-Id.—Adsorption of 5936-Id⁺ B6 anti-CBA MIg preparations on CBA (IA^k) spleen cells demonstrated that CBA antibodies were 5936-Id^?. It is dicussed whether 5936-Id⁺, IgG₁ molecules in B6 anti-CBA sera are anti-(anti-CBA) antibodies or nonspecific antibodies, the production of which is augmented by immunization with IA^k alloantigen.     

Anaphylatoxin-mediated regulation of human and murine immune responses

C3a and C5a derived from the human complement components C3 and C5, respectively, were found to possess immunoregulatory activities. C3a was found to be capable of suppressing both antigen-specific and polyclonal antibody responses. In contrast, C3a was unable to suppress antigen- or mitogen-induced B or T cell proliferative responses. Helper T cells were found to be the target of C3a-mediated immunosuppression. Suppression occurred via the generation of suppressor T cells. In contrast to the results obtained with C3a, C5a was found to augment both antigen-specific and non-specific in vitro humoral immune responses. Moreover, C5a potentiated antigen- and alloantigen-induced T cell proliferative responses. As opposed to C3ades Arg-77, C5ades Arg retained all of the immunoregulatory activity associated with the intact molecule. Helper T cells are required for C5a-mediated potentiation of the Fc fragment-mediated polyclonal antibody response. Substitution for T cells by a soluble T cell-replacing factor rendered lymphocytes refractory to the enhancing properties of C5a.     

Ubiquitin enzymes in the regulation of immune responses

Ubiquitination plays a central role in the regulation of various biological functions including immune responses. Ubiquitination is induced by a cascade of enzymatic reactions by E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase, and reversed by deubiquitinases. Depending on the enzymes, specific linkage types of ubiquitin chains are generated or hydrolyzed. Because different linkage types of ubiquitin chains control the fate of the substrate, understanding the regulatory mechanisms of ubiquitin enzymes is central. In this review, we highlight the most recent knowledge of ubiquitination in the immune signaling cascades including the T cell and B cell signaling cascades as well as the TNF signaling cascade regulated by various ubiquitin enzymes. Furthermore, we highlight the TRIM ubiquitin ligase family as one of the examples of critical E3 ubiquitin ligases in the regulation of immune responses.     

具年龄结构的种群在破碎化生境中的空间分布模型

随着人类和其他生物赖以生存的环境破碎化程度的加剧,许多以前是连续分布的物种,目前不得不在破碎化生境(斑块)中求生存,所以,种群在破碎化生境(斑块)中分布问题的研究对生物保护和生境重建意义重大．本文运用Leslie矩阵和Markov链建立了一个具年龄结构的种群在破碎化生境中随时间动态变化的分布模型,讨论了种群在该生境中持续存在以及灭绝的条件．     

Lectin-induced regulation of human thymus-independent anti-TNP responses in vitro

Recently we showed that human hapten-specific T cell-independent (TI) antibody responses could be elicited in vitro with the antigen trinitrophenylated Brucella abortus (TNP-Ba). Although by definition T cells are not required for TI responses, they have also shown capable of regulating such responses in the mouse. In this study we examine the ability of the T cell lectins Con A and PHA to modulate TI responses of human tonsil cells. Addition of the lectins to cultures on day 0 or day 3 resulted in inhibition (greater than 90%) or enhancement (greater than 150%) of the anti-TNP PFC response, respectively. The inhibition was only apparent if the lectins were added at the onset of culture but not 24 hr later, and was T cell-dependent, because T cell-depleted cultures (less than 0.5% E-rosetting cells) could not be inhibited. The enhancement observed was even greater in T cell-depleted cultures and was antigen-specific because TNP-SRBC but not PC-SRBC targets were lysed and the PFC were inhibited by soluble TNP (greater than 70%). This finding suggested that anti-TNP PFC precursors were proliferating more vigorously or that additional, previously antigen-insensitive cells were being recruited in the presence of lectin.