Ignorance can be evolutionarily beneficial

Information is increasingly being viewed as a resource used by organisms to increase their fitness. Indeed, it has been formally shown that there is a sensible way to assign a reproductive value to information and it is non‐negative. However, all of this work assumed that information collection is cost‐free. Here, we account for such a cost and provide conditions for when the reproductive value of information will be negative. In these instances, counterintuitively, it is in the interest of the organism to remain ignorant. We link our results to empirical studies where Bayesian behavior appears to break down in complex environments and provide an alternative explanation of lowered arousal thresholds in the evolution of sleep.     

Bacteria can be selected to help beneficial plasmids spread

A recent commentary raised concerns about aspects of the model and assumptions used in a previous study which demonstrated that selection can favor chromosomal alleles that confer higher plasmid donation rates. Here, the authors of that previous study respond to the concerns raised.

In our original work [1], we demonstrated experimentally that selection can favor chromosomal alleles that confer higher plasmid donation rates, given the plasmid is beneficial and the recipient has an elevated chance of carrying the donor allele (i.e., preferential donation to kin). Our experiments demonstrated this effect via 2 mechanisms of preferential donation: biased conjugation rates and structured populations. We interpreted these results through the lens of kin selection theory (benefits via horizontal gene transfer to kin), supported by simulations and an analytical fitness function model. These results hold importance by outlining that the evolution of plasmid transfer rates (a key aspect of the antibiotic resistance crisis) is not necessarily the sole product of selection on the plasmid itself and forms part of a broader series of papers from our labs investigating the sociomicrobiology of plasmids [2–4].A new commentary raises concerns over our fitness function model, flagging issues with both the structure of the model and assumptions made in our analysis [5]. We stand by the general conclusions of our work but accept that our fitness function and stated analysis assumptions could be better formulated. Our initial fitness function is heuristic in the sense it was designed to capture general processes acting on the fitness of individuals, dependent on the plasmid and donor allele status—without explicitly modeling the myriad demographic events of dispersal, reproduction, conjugation, and death that result in selective shifts across a metapopulation of cells. Specifically, we captured the “force of infection” faced by an uninfected cell as the product of average plasmid prevalence and average donor allele prevalence in the local patch (p_jq_j; see commentary for notation details). We agree with the authors that this force of infection is better phrased as the average of the product ((1/N)∑p_ij q_ij), in part because this avoids the potential pathology under limit conditions described by the authors, but also because this approach better highlights that the particular social trait in question is an “other only” cooperative trait [6], illustrated by commentary equation [2], where transmission to self and transmission to others are separated. This separation has the important consequence of highlighting that unlike many microbial social traits where benefits accrue to a group (including self), a cooperative plasmid donor trait can only benefit other cells that lack the plasmid. Given established costs of donation (e.g., see figure S2 in our original article), this defines our “donor” behavior as an altruistic trait, which can, therefore, only be favored by selection given nonrandom interactions among individuals (e.g., [7]).Our experimental results outline 2 mechanisms of nonrandom interactions: preferential donation to kin and population structure. Each of these mechanisms will generate positive covariances between focal individual q_ij and non-self-recipient q_j donor allele states (cov(q_j, q_ij) > 0). The pathway via preferential donation to kin (order-of-magnitude differences according to our analyses and more recent measurements among lineages coexisting within natural populations [8]) will also likely generate positive covariances between donor and recipient abilities (cov(s_ij, q_ij) > 0). In contrast, to arrive at the result that selection always works against plasmid donor alleles (equation [4]), the commentary makes the assumption that both of the above covariances are zero. We suggest that the additional analyses begun by the authors are an exciting starting point to better map selection on donor alleles, under a broader array of defined assumptions on cell–cell and gene–gene structure, ideally informed by data on structures found in natural bacterial populations.     

Prostate-specific antigen screening of workers under the age of 40 in Japan

Background: There is no agreement on the usefulness of the prostate-specific antigen (PSA) test for prostate cancer screening in young men in Japan. We believe that medical check-up departments in hospitals conduct prostate cancer screening in subjects under 40 years of age undergoing intensive health check-up for commercial reasons, and speculate that some medical doctors provide tacit consent for this action. To understand the prevalence of PSA testing in young men, the authors examined the age distribution of workers who underwent the PSA test. Methods: The authors used the 2009 intensive health check-up data of male workers aged 30–65 years (n = 298) in a car-manufacturing company to investigate the status of prostate-cancer screening in young men. Multiple comparison was conducted by Tukey's method when the analysis of variance revealed significant difference. Results: According to the frequency distribution of age, 15.8% of the subjects were under 40 years of age. The mean PSA value increased with age, ranging from 1.0 ng/mL in subjects in their 30s’, to 2.0 ng/mL in subjects in their 60s’. The mean PSA level in subjects in their 60s’ was significantly higher than that in subjects in their 30s’ and 40s’. The percentage of subjects with serum PSA levels of 4 ng/mL or higher in subjects in their 30s’, 40s’, 50s’ and 60s’ were 2.1% (1/47), 1.6% (2/125), 4.4% (5/114) and 8.3% (1/12), respectively. Conclusions: One-sixth of male workers attending the health check-up program were under 40 years of age. According to the criteria of the Japanese Urological Association, this examination program included younger subjects who were not candidates for PSA screening.     

Maternally transmitted parasite defence can be beneficial in the absence of parasites

Newborn animals do not have a fully functional immune system and are thus impaired in their ability to fight parasites. Mothers can therefore increase the survival probability of their young by providing them with passive immunity, e.g. in the form of maternal antibodies transferred via the placenta or the eggs. The maternal responses are only induced when parasites are present, and have been observed not only in vertebrates but also in invertebrates. However, while these parasite-induced maternal effects are known to reduce the harmful effects of common parasites, they may also impose costs for the young, either because the maternal response impairs parental performance, or because maternally transmitted products moderate offspring development. We experimentally tested these two hypotheses in a wild great tit population. We exposed birds to a common ectoparasite before egg-laying to induce the maternal response, and thereafter separated egg-mediated maternal effects from effects on post-laying parental performance by cross-fostering whole clutches. To assess the costs of this response without its confounding benefits, we kept nests free of parasites after hatching. Since the costs of maternal effects can be expressed differently under relaxed and harsh rearing conditions, we simultaneously manipulated clutch size. First, parasite-exposed parents raised lighter young, suggesting that parasite defence or the induced maternal response are costly to the parents and reduce their capacity to raise young. Second, under relaxed but not under harsh rearing conditions, young with the flea-induced maternal effect were heavier and were in better body condition than controls, suggesting that the maternally transferred products can be allocated to physiological functions beyond parasite defence.     

Hypothesis: synthetic aging antigen can be used to manipulate cellular lifespan

Physiologic removal of old and damaged erythrocytes, platelets, and other terminally differentiated cells is initiated by the appearance of an aging antigen that marks them for death by initiating the binding of IgG autoantibody and subsequent removal by phagocytes. We have developed a synthetic aging antigen peptide that blocks binding of IgG to senescent cells in vitro. We hypothesize that the synthetic antigen can be used to prevent cell destruction in diseases such as autoimmune hemolytic anemias and idiopathic thrombocytopenia purpura, and that the antigen itself can be used to manipulate cellular lifespan in vivo.     

Cardiovascular response to exercise in younger and older men

Measurements of cardiac performance for humans at various ages is influenced by the variable examined, the population and techniques employed, and the factors that co-vary with age, including the presence of disease and physical conditioning. Interstudy differences in the extent to which occult coronary disease is present in older subjects and in the level of physical conditioning among subjects may underlie the variable perspectives contained in the literature of how aging affects cardiovascular function. In carefully screened, highly motivated but not athletically trained community-dwelling subjects, resting cardiovascular parameters are not age related except for systolic blood pressure, which increases with age. During vigorous exercise the mechanisms used to achieve a high level of cardiac output shift from a dependence on a catecholamine-mediated increase in heart rate and inotropy to a dependence on the Frank Starling mechanism. One reason for the age difference in cardiovascular response to exercise may be a diminished responsiveness to beta-adrenergic stimulation in these subjects. In other elderly subjects who cannot exercise to high work loads, a decline in stroke volume as well as heart rate at peak exercise has been observed. Whether the inability of these individuals to augment stroke volume is caused by a decrease in the ability of the heart to increase diastolic filling, by a decrease in systolic pump function caused by an increased afterload, by intrinsic myocardial contractile defects, or by a greater diminution of the cardiovascular response to beta-adrenergic stimuli is presently unknown.     

IgG-mediated systemic anaphylaxis to protein antigen can be induced even under conditions of limited amounts of antibody and antigen

Systemic anaphylaxis is an acute, severe, and potentially fatal allergic reaction. Two classes of antibodies, IgE and IgG, contribute to the development of anaphylaxis in mice, through different mechanisms with distinct usage of effector cells and chemical mediators. Larger quantities of antibody and antigen are reportedly required to induce IgG-mediated anaphylaxis than IgE-mediated one, suggesting that the former may not happen as frequently as the latter in real life. To readdress this issue, we established in the present study a novel mouse model of passive IgG-mediated systemic anaphylaxis to a native protein antigen, ovalbumin (OVA), rather than artificially haptenated protein antigens used in previous studies. Passive sensitization of mice with a cocktail of but not individual IgG1 mAbs specific to distinct OVA epitopes elicited systemic anaphylaxis in response to OVA challenge. Importantly, much smaller doses of antibody and antigen than previously reported were sufficient for the induction of IgG-mediated systemic anaphylaxis. Moreover, a relatively small dose of antigen could induce severe anaphylaxis through both IgE- and IgG-mediated mechanisms when mice had been passively sensitized with antigen-specific IgE and IgG. These results strongly suggest that IgG-mediated systemic anaphylaxis is not rare among antibody-mediated systemic anaphylaxis, in contrast to previous thought, and significantly contributes to active systemic anaphylaxis in real life, at least in mice.     

Protective immunity to progressive tumors can be induced by antigen presented on regressor tumors

Immunization of animals with 1591-RE tumor cells, a highly immunogenic UV-induced epithelia cell tumor from C3H/HeN mice, that were haptenated with trinitrophenol (TNP) leads to protective immunity against a challenge of TNP-haptenated 3152-PRO tumor cells, a progressive highly malignant. MCA-induced fibrosarcoma from syngeneic mice. Animals that rejected TNP-1591-RE and subsequently TNP-3152-PRO tumor cells showed increased tumor-specific resistance to another challenge of 3152-PRO tumor cells, even when these fibrosarcoma cells had not been haptenated with TNP. Induction of protection required the presence of TNP-hapten groups on both 1591-RE and 3152-PRO during the initial immunization, and could be induced by immunization with other haptenated syngeneic highly immunogenic regressor tumor lines. In addition, TNP-haptenated progressor variants of the 1591-RE were ineffective in generating protection, suggesting that the immunogenicity of the haptenated tumor used for the initial immunization was a determining factor in whether or not protective immunity against the highly malignant tumor was later generated. Protection required at least two T cell types: a Lyt-1-2+ T cells, and a Lyt-1+2- T cell that also expressed I-J determinants and was Vicia villosa lectin adherent, suggesting it was not a classical helper T cell. These results suggest that presentation of a hapten by highly immunogenic tumor cells can lead to enhanced protective immunity to poorly immunogenic noncross-reactive tumors that co-express the same hapten, and rejection of these haptenated poorly immunogenic tumors leads to enhanced protection against a subsequent challenge of the same, but not noncross-reactive progressor tumors.     

Acute hormonal responses to heavy resistance exercise in younger and older men

The purpose of this investigation was to examine the acute responses of several hormones [total and free testosterone (TT and FT, respectively), adrenocorticotropic hormone (ACTH), cortisol (C), growth hormone (GH), and insulin (INS)] to a single bout of heavy resistance exercise (HRE). Eight younger [30-year (30y) group] and nine older [62-year (62y) group] men matched for general physical characteristics and activity levels performed four sets of ten repetitions maximum (RM) squats with 90 s rest between sets. Blood samples were obtained from each subject via an indwelling cannula with a saline lock pre-exercise, immediately post-exercise (IP), and 5, 15 and 30 min post-exercise. Levels of TT, FT, ACTH, C and lactate significantly increased after HRE for both groups. Pre-HRE pairwise differences between groups were noted only for FT, while post-HRE pairwise differences were found for TT, FT, GH, glucose and lactate. Area under the curve analysis showed that the 30y group had a significantly higher magnitude of increase over the entire recovery period (IP, 5, 15, and 30 min post-exercise) for TT, FT, ACTH and GH. Few changes occurred in the INS response with the only change being that the 62y group demonstrated a decrease IP. Lactate remained elevated at 30 min post-HRE. This investigation demonstrates that age-related differences occur in the endocrine response to HRE, and the most striking changes appear evident in the FT response to HRE in physically active young and older men. Accepted: 11 June 1997     

Drought may be beneficial to the competitive advantage of Amaranthus spinosus

干旱利于刺苋的竞争优势 干旱可以影响入侵植物的生长和土壤酶活性。因此,非常有必要评估干旱背景下入侵植物的竞争优势以及入侵植物和干旱对土壤酶活性的影响。本研究旨在分析干旱背景下起源于热带美洲的入侵植物刺苋(Amaranthus spinosus)与本地植物苋菜(Amaranthus tricolor)共存时的竞争优势和土壤酶活性。通过栽植实验进行刺苋与苋菜的竞争共栽培,并进行不同水平的干旱处理,即：(i)对照;(ii)轻度干旱;(iii)重度干旱。实验结束后测定两种苋属植物的功能性状、渗透调节、抗氧化酶活性以及土壤pH、电导率、土壤微生物生物量碳含量和土壤酶活性。干旱背景下,刺苋的相对竞争强度和相对优势度均高于苋菜。因此,干旱利于刺苋的竞争优势。干旱背景下,刺苋的土壤水溶性盐含量和蔗糖水解能力均大于苋菜。而较高的土壤水溶性盐含量和蔗糖水解能力利于刺苋对养分的获取和利用。     

Thymidine incorporation is highly predictive of colony formation and can be used for high-throughput screening

The primary goal of anticancer chemotherapy is to kill cancer cells. Therefore, it is of critical importance that any assay that is used to determine the toxicity of a potential anticancer drug accurately measures viability. While colony formation is widely regarded as the most accurate measure of viability following drug treatment, it is laborious, time consuming, and difficult to carry out with non-adherent cells. For these reasons, it is not suitable for moderate- to high-throughput screening applications. We sought to identify a convenient and reliable assay that would accurately reproduce colony formation results and be amenable to high-throughput applications. Here, we describe a modification of the 3H-thymidine incorporation assay that meets these criteria. The assay can be carried out in 96-well plates with minimal handling of reagents and media. It can be performed with non-adherent and adherent cell lines. Most importantly, LC50 values obtained with this assay show excellent agreement with colony formation results. Taken together, these advantages make the modified 3H-thymidine incorporation assay well suited for high-throughput viability assays in anticancer drug discovery and development.     

Salmonella escape from antigen presentation can be overcome by targeting bacteria to Fc gamma receptors on dendritic cells

Dendritic cells (DCs) are professional APCs with the unique ability to activate naive T cells, which is required for initiation of the adaptive immune response against pathogens. Therefore, interfering with DC function would be advantageous for pathogen survival and dissemination. In this study we provide evidence suggesting that Salmonella enterica serovar typhimurium, the causative agent of typhoid disease in the mouse, interferes with DC function. Our results indicate that by avoiding lysosomal degradation, S. typhimurium impairs the ability of DCs to present bacterial Ags on MHC class I and II molecules to T cells. This process could correspond to a novel mechanism developed by this pathogen to evade adaptive immunity. In contrast, when S. typhimurium is targeted to FcgammaRs on DCs by coating bacteria with Salmonella-specific IgG, bacterial Ags are efficiently processed and presented on MHC class I and class II molecules. This enhanced Ag presentation leads to a robust activation of bacteria-specific T cells. Laser confocal microscopy experiments show that virulent S. typhimurium is rerouted to the lysosomal degradation pathway of DCs when internalized through FcgammaR. These observations are supported by electron microscopy studies demonstrating that internalized S. typhimurium shows degradation signs only when coated with IgG and captured by FcgammaRs on DCs. Therefore, our data support a potential role for bacteria-specific IgG on the augmentation of Ag processing and presentation by DCs to T cells during the immune response against intracellular bacteria.     

Polyoma middle-sized T antigen can be phosphorylated on tyrosine at multiple sites in vitro

The polyoma middle-sized T antigen (MT antigen) is associated with a protein kinase activity which phosphorylates tyrosine residues in polyoma T antigens in vitro. We have studied the sites of tyrosine phosphorylation of MT antigens phosphorylated in immunoprecipitates or in soluble form after partial purification by immunoaffinity chromatography. By analyzing the amino acid sequences of tryptic peptides of MT antigen, and by analyzing deletion mutant MT antigens, we have identified two major sites of phosphorylation in MT antigen, tyrosines 250 and 315. Additional sites were phosphorylated under some conditions. A synthetic peptide (Glu.Glu.Glu.Glu.Tyr.Met.Pro.Met.Glu), corresponding to the sequence around tyrosine 315, was phosphorylated when added to immunoprecipitates containing MT antigen.     

Triple-site antigen capture ELISA for human myoglobin can be more effective than double-site assay

Using a panel of monoclonal antibodies against human myoglobin (Mb), we have shown that the sensitivity of antigen-capture ELISA can be significantly increased by simultaneous immobilization of two cooperating capture monoclonal antibodies on a solid phase. This method ("triple-site ELISA") uses three monoclonal antibodies to different epitopes of the same antigen (two capture/one tracer) unlike the traditional double-site assay using one capture and one tracer monoclonal antibody. We developed double- and triple-site ELISA for Mb by varying the capture and tracer monoclonal antibodies. Triple-site assays showed 4-6-fold increase in sensitivity compared to the double-site assays. A model for this effect is suggested; according to the model, in triple-site ELISA, high-affinity cyclic configurations can be formed by an antigen, two capture monoclonal antibodies, and the surface of the solid phase.     

Constitutive competition by self proteins for antigen presentation can be overcome by receptor-enhanced uptake

The cells recognize a bimolecular ligand composed of a self Ia molecule and a fragment of foreign Ag that has been processed by an APC. The effect of self proteins on the processing and presentation of foreign Ag was examined in order to ascertain the mechanisms for competition between foreign and self Ag. How this competition can be overcome to allow an efficient immune response was also examined. Normal mouse serum proteins (NMS) compete for the processing and presentation of the foreign Ag bovine RNase by APC. This competition could have occurred at any of three levels in the APC: 1) Ag uptake, 2) Ag processing, or 3) the binding of Ag to an Ia molecule. No competition for either the uptake or the processing of RNase by self proteins could be demonstrated. However, self peptides do compete with foreign Ag by binding directly to Ia molecules, as has been shown previously. Thus, the observed inhibition by NMS of Ag presentation occurred because of competition for binding to the Ia molecule. We hypothesized that during the generation of an immune response this competition is overcome by enhanced uptake of foreign Ag. To test this, we compared the ability of NMS to compete for the presentation of RNase when it entered the APC via fluid-phase pinocytosis or through receptor-mediated uptake via the mannose receptor. When the RNase entered the APC through the mannose receptor, the ability of NMS to compete was dramatically reduced. Thus, self proteins constitutively compete for the presentation of foreign Ag at the level of binding to an Ia molecule, and this competition can be overcome by receptor-mediated uptake of the Ag.