Group Cooperation without Group Selection: Modest Punishment Can Recruit Much Cooperation

Humans everywhere cooperate in groups to achieve benefits not attainable by individuals. Individual effort is often not automatically tied to a proportionate share of group benefits. This decoupling allows for free-riding, a strategy that (absent countermeasures) outcompetes cooperation. Empirically and formally, punishment potentially solves the evolutionary puzzle of group cooperation. Nevertheless, standard analyses appear to show that punishment alone is insufficient, because second-order free riders (those who cooperate but do not punish) can be shown to outcompete punishers. Consequently, many have concluded that other processes, such as cultural or genetic group selection, are required. Here, we present a series of agent-based simulations that show that group cooperation sustained by punishment easily evolves by individual selection when you introduce into standard models more biologically plausible assumptions about the social ecology and psychology of ancestral humans. We relax three unrealistic assumptions of past models. First, past models assume all punishers must punish every act of free riding in their group. We instead allow punishment to be probabilistic, meaning punishers can evolve to only punish some free riders some of the time. This drastically lowers the cost of punishment as group size increases. Second, most models unrealistically do not allow punishment to recruit labor; punishment merely reduces the punished agent’s fitness. We instead realistically allow punished free riders to cooperate in the future to avoid punishment. Third, past models usually restrict agents to interact in a single group their entire lives. We instead introduce realistic social ecologies in which agents participate in multiple, partially overlapping groups. Because of this, punitive tendencies are more expressed and therefore more exposed to natural selection. These three moves toward greater model realism reveal that punishment and cooperation easily evolve by direct selection—even in sizeable groups.     

Cooperation between Apoptotic and Viable Metacyclics Enhances the Pathogenesis of Leishmaniasis

Mimicking mammalian apoptotic cells by exposing phosphatidylserine (PS) is a strategy used by virus and parasitic protozoa to escape host protective inflammatory responses. With Leishmania amazonensis (La), apoptotic mimicry is a prerogative of the intramacrophagic amastigote form of the parasite and is modulated by the host. Now we show that differently from what happens with amastigotes, promastigotes exposing PS are non-viable, non-infective cells, undergoing apoptotic death. As part of the normal metacyclogenic process occurring in axenic cultures and in the gut of sand fly vectors, a sub-population of metacyclic promastigotes exposes PS. Apoptotic death of the purified PS-positive (PS^POS) sub-population was confirmed by TUNEL staining and DNA laddering. Transmission electron microscopy revealed morphological alterations in PS^POS metacyclics such as DNA condensation, cytoplasm degradation and mitochondrion and kinetoplast destruction, both in in vitro cultures and in sand fly guts. TUNEL^POS promastigotes were detected only in the anterior midgut to foregut boundary of infected sand flies. Interestingly, caspase inhibitors modulated parasite death and PS exposure, when added to parasite cultures in a specific time window. Efficient in vitro macrophage infections and in vivo lesions only occur when PS^POS and PS-negative (PS^NEG) parasites were simultaneously added to the cell culture or inoculated in the mammalian host. The viable PS^NEG promastigote was the infective form, as shown by following the fate of fluorescently labeled parasites, while the PS^POS apoptotic sub-population inhibited host macrophage inflammatory response. PS exposure and macrophage inhibition by a subpopulation of promastigotes is a different mechanism than the one previously described with amastigotes, where the entire population exposes PS. Both mechanisms co-exist and play a role in the transmission and development of the disease in case of infection by La. Since both processes confer selective advantages to the infective microorganism they justify the occurrence of apoptotic features in a unicellular pathogen.     

In Your Face: Risk of Punishment Enhances Cognitive Control and Error-Related Activity in the Corrugator Supercilii Muscle

Cognitive control is needed when mistakes have consequences, especially when such consequences are potentially harmful. However, little is known about how the aversive consequences of deficient control affect behavior. To address this issue, participants performed a two-choice response time task where error commissions were expected to be punished by electric shocks during certain blocks. By manipulating (1) the perceived punishment risk (no, low, high) associated with error commissions, and (2) response conflict (low, high), we showed that motivation to avoid punishment enhanced performance during high response conflict. As a novel index of the processes enabling successful cognitive control under threat, we explored electromyographic activity in the corrugator supercilii (cEMG) muscle of the upper face. The corrugator supercilii is partially controlled by the anterior midcingulate cortex (aMCC) which is sensitive to negative affect, pain and cognitive control. As hypothesized, the cEMG exhibited several key similarities with the core temporal and functional characteristics of the Error-Related Negativity (ERN) ERP component, the hallmark index of cognitive control elicited by performance errors, and which has been linked to the aMCC. The cEMG was amplified within 100 ms of error commissions (the same time-window as the ERN), particularly during the high punishment risk condition where errors would be most aversive. Furthermore, similar to the ERN, the magnitude of error cEMG predicted post-error response time slowing. Our results suggest that cEMG activity can serve as an index of avoidance motivated control, which is instrumental to adaptive cognitive control when consequences are potentially harmful.     

Chronic Exposure to Combined Carcinogens Enhances Breast Cell Carcinogenesis with Mesenchymal and Stem-Like Cell Properties

Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.     

An Evolutionary Model of Cooperation,Fairness and Altruistic Punishment in Public Good Games

We identify and explain the mechanisms that account for the emergence of fairness preferences and altruistic punishment in voluntary contribution mechanisms by combining an evolutionary perspective together with an expected utility model. We aim at filling a gap between the literature on the theory of evolution applied to cooperation and punishment, and the empirical findings from experimental economics. The approach is motivated by previous findings on other-regarding behavior, the co-evolution of culture, genes and social norms, as well as bounded rationality. Our first result reveals the emergence of two distinct evolutionary regimes that force agents to converge either to a defection state or to a state of coordination, depending on the predominant set of self- or other-regarding preferences. Our second result indicates that subjects in laboratory experiments of public goods games with punishment coordinate and punish defectors as a result of an aversion against disadvantageous inequitable outcomes. Our third finding identifies disadvantageous inequity aversion as evolutionary dominant and stable in a heterogeneous population of agents endowed initially only with purely self-regarding preferences. We validate our model using previously obtained results from three independently conducted experiments of public goods games with punishment.     

Combined Administration with DNA Encoding Vesicular Stomatitis Virus G Protein Enhances DNA Vaccine Potency

DNA vaccines have recently emerged at the forefront of approaches to harness the immune system in the prevention and treatment of viral infections, as well as the prevention and treatment of cancers. However, these vaccines suffer from limited efficacy since they often fail to produce significant antigen-specific CD8⁺ T-cell responses. We report here a novel concept for DNA vaccine design that exploits the unique and powerful ability of viral fusogenic membrane glycoproteins (FMGs) to couple concentrated antigen transfer to dendritic cells (DCs) with local induction of the acute inflammatory response. Intramuscular administration into mice by electroporation technology of a plasmid containing the FMG gene from vesicular stomatitis virus (VSV-G)—together with DNA encoding the E7 protein of human papillomavirus type 16, a model cervical cancer antigen—elicited robust E7-specific CD8⁺ T-cell responses, as well as therapeutic control of E7-expressing tumors. This effect could potentially be mediated through the immunogenic form of cellular fusion and necrosis induced by VSV-G, which in a concerted fashion provokes leukocyte infiltration into the inoculation site, enhances cross-presentation of antigen to DCs, and stimulates them to mature efficiently. Thus, the incorporation of FMGs into DNA vaccines holds promise for the successful control of viral infections and cancers in the clinic.Due to their safety, low manufacturing cost, and ease of production, DNA vaccines have emerged as one of the most attractive approaches to prevent and treat viral infections, as well as cancers with defined tumor-associated antigens. Several studies have demonstrated that DNA vaccines can produce significant CD8⁺ T-cell-mediated immunity—which is often essential in the elimination of pathogens and malignancies—together with therapeutic benefit in various animal models of disease (4, 21-23, 29). However, DNA vaccines have achieved limited success in the clinic, since they generally elicit limited CD8⁺ T-cell responses in humans despite repeated high-dose administration (15, 28). Therefore, there is a critical need to develop DNA vaccines which generate these types of responses.DNA vaccines are commonly delivered by inoculation into skeletal muscle, where myocytes uptake them and express their encoded antigen. Myocytes, however, lack major histocompatibility complex (MHC) class II and costimulatory molecules and, as a result, have poor ability to prime naive T cells. Thus, the potency of DNA vaccines depends on sequential phases of antigen transfer from myocytes to sentinel dendritic cells (DCs), followed in close succession by the maturation of these DCs. The DCs then migrate to lymphoid organs, where they can present the antigen to and activate cognate naive CD8⁺ T cells (11). In the absence of either of these phases, either a null or a tolerogenic immune response is generated.One of the major challenges to the generation of CD8⁺ T-cell responses is therefore the design of vaccines that efficiently target antigen to and stimulate the maturation of DCs in a concerted manner. We hypothesized that this could be accomplished through the induction of an inflammatory form of myocyte death with concentrated antigen release to DCs upon DNA immunization. Viral fusogenic membrane glycoproteins (FMGs) represent ideal agents for eliciting such an effect. It has been shown that FMGs induce the fusion of cells into large multinucleated syncytia, which are lysed rapidly by nonapoptotic mechanisms (1) and in the process shed exosomes from the membrane (2). We reasoned that, since nonapoptotic death has been linked to stimulation of the innate immune system (25) and since exosomes have been reported to contain antigen that can be readily taken up by DCs (30), FMGs may bolster the release of antigens encoded by the DNA vaccine, leading to enhanced antigen-specific CD8⁺ T-cell responses.We have previously created and characterized a panel of DNA vaccines targeting the E7 oncoprotein of human papillomavirus (HPV) type 16, a model cervical cancer antigen. Because E7 is required for the maintenance of the transformed cellular phenotype and is expressed in virtually all cases of cervical cancers, it provides an ideal molecular target against which to apply our vaccination approach. In head-to-head comparisons of these vaccines, we showed that one particular construct, CRT/E7, could generate the most potent immunological and therapeutic effect against E7-expressing tumors (14). However, although CRT/E7 can cure mice with small tumors, it invariably fails to control more advanced forms of disease. In light of this obstacle, we sought to determine whether VSV-G could render CRT/E7 therapeutically effective against otherwise refractory E7-expressing tumors. We have previously characterized the growth kinetics of one such aggressive tumor model, TC-1, in mice and observed consistently that 1 week after subcutaneous challenge with 5 × 10⁵ cancerous cells, the mass becomes clearly detectable by palpation and visual inspection, and vaccination with CRT/E7—even with repeated high dose administration—has negligible beneficial effect on disease progression or animal survival. At this point, we considered the cancer to be sufficiently advanced, and this timeline was therefore adopted for the tumor treatment experiments in the present study.In the present study, we explored whether combined administration with VSV-G could successfully control the growth of aggressive TC-1 tumors refractory to treatment with CRT/E7 alone, and potential mechanisms by which this might be achieved. Collectively, our data indicate that incorporation of FMGs into DNA vaccines represents a therapeutically promising strategy for the generation of antigen-specific T-cell-mediated immunity against viral infections and cancer.     

Domestic Dogs Use Contextual Information and Tone of Voice when following a Human Pointing Gesture

Domestic dogs are skillful at using the human pointing gesture. In this study we investigated whether dogs take contextual information into account when following pointing gestures, specifically, whether they follow human pointing gestures more readily in the context in which food has been found previously. Also varied was the human''s tone of voice as either imperative or informative. Dogs were more sustained in their searching behavior in the ‘context’ condition as opposed to the ‘no context’ condition, suggesting that they do not simply follow a pointing gesture blindly but use previously acquired contextual information to inform their interpretation of that pointing gesture.Dogs also showed more sustained searching behavior when there was pointing than when there was not, suggesting that they expect to find a referent when they see a human point. Finally, dogs searched more in high-pitched informative trials as opposed to the low-pitched imperative trials, whereas in the latter dogs seemed more inclined to respond by sitting. These findings suggest that a dog''s response to a pointing gesture is flexible and depends on the context as well as the human''s tone of voice.     

Joint Cognition: Thought Contagion and the Consequences of Cooperation when Sharing the Task of Random Sequence Generation

Generating random number sequences is a popular psychological task often used to measure executive functioning. We explore random generation under “joint cognition” instructions; pairs of participants take turns to compile a shared response sequence. Across three studies, we point to six key findings from this novel format. First, there are both costs and benefits from group performance. Second, repetition avoidance occurs in dyadic as well as individual production settings. Third, individuals modify their choices in a dyadic situation such that the pair becomes the unit of psychological function. Fourth, there is immediate contagion of sequence stereotypy amongst the pairs (i.e., each contributor “owns” their partner’s response). Fifth, dyad effects occur even when participants know their partner is not interacting with them (Experiment 2). Sixth, ironically, directing participants’ efforts away from their shared task responsibility can actually benefit conjoint performance (Experiment 3). These results both constrain models of random generation and illuminate processes of joint cognition.     

舒芬太尼联合地塞米松对肺癌患者气管拔管时血流动力学的影响

目的：观察联合应用舒芬太尼和地塞米松对肺癌患者双腔支气管拔管时血流动力学的影响。方法：选择在全麻下行肺癌根治术的患者60例,ASA分级Ⅰ-Ⅱ级,随机分为三组,舒芬太尼组（s组）、舒芬太尼联合地塞米松组（SD组）和生理盐水组（N组）,每组20例。SD组于麻醉诱导前静脉推注10 mg地塞米松,手术结束前30 min静脉推注0.15μg/kg舒芬太尼;S组、N组分别于手术结束前30 min静脉推注0.15μg/kg舒芬太尼和2 mL生理盐水;记录麻醉诱导前（T0）、拔管即刻（T1）、拔管后3 min（T2）及拔管后5 min（T3）时的心率（HR）,平均动脉压（MAP）,并计算心率与收缩压的乘积（RPP）;术毕后麻醉恢复时间：自主呼吸恢复时间、睁眼时间、拔管时间。结果：与麻醉诱导前（T0）相比,S组、SD组在手术拔管期各时间点的MAP,HR,RPP变化幅度明显低于N组（P〈0.05）;SD组较S组血流动力学更加平稳（P〈0.05）。S组、SD组虽然自主呼吸恢复时间和睁眼时间与N组比较有所延长,但拔管时间并无显著性差（P〉0.05）,且S组、SD组比较无统计学差异（P〉0.05）。结论：应用舒芬太尼联合地塞米松可以使双腔支气管导管拔管时的血流动力学更加平稳。     

Combined Treatment with Cadmium and Zinc Enhances Lateral Root Development by Regulating Auxin Redistribution and Cell-Cycle Gene Expression in Rice Seedlings

Russian Journal of Plant Physiology - Enhanced lateral root (LR) development is of critical importance for rice plants adapting to heavy-metal-stress conditions. LR development is affected by heavy...     

Increased Anticancer Efficacy of Intravesical Mitomycin C Therapy when Combined with a PCNA Targeting Peptide

Non–muscle-invasive bladder cancers (NMIBCs) are tumors confined to the mucosa or the mucosa/submucosa. An important challenge in treatment of NMIBC is both high recurrence and high progression rates. Consequently, more efficacious intravesical treatment regimes are in demand. Inhibition of the cell’s DNA repair systems is a new promising strategy to improve cancer therapy, and proliferating cell nuclear antigen (PCNA) is a new promising target. PCNA is an essential scaffold protein in multiple cellular processes including DNA replication and repair. More than 200 proteins, many involved in stress responses, interact with PCNA through the AlkB homologue 2 PCNA-interacting motif (APIM), including several proteins directly or indirectly involved in repair of DNA interstrand crosslinks (ICLs). In this study, we targeted PCNA with a novel peptide drug containing the APIM sequence, ATX-101, to inhibit repair of the DNA damage introduced by the chemotherapeutics. A bladder cancer cell panel and two different orthotopic models of bladder cancer in rats, the AY-27 implantation model and the dietary BBN induction model, were applied. ATX-101 increased the anticancer efficacy of the ICL-inducing drug mitomycin C (MMC), as well as bleomycin and gemcitabine in all bladder cancer cell lines tested. Furthermore, we found that ATX-101 given intravesically in combination with MMC penetrated the bladder wall and further reduced the tumor growth in both the slow growing endogenously induced and the rapidly growing transplanted tumors. These results suggest that ATX-101 has the potential to improve the efficacy of current MMC treatment in NMIBC.     

To Punish or to Leave: Distinct Cognitive Processes Underlie Partner Control and Partner Choice Behaviors

When a cooperative partner defects, at least two types of response are available: Punishment, aimed at modifying behavior, and ostracism, aimed at avoiding further social interaction with the partner. These options, termed partner control and partner choice, have been distinguished at behavioral and evolutionary levels. However, little work has compared their cognitive bases. Do these disparate behaviors depend on common processes of moral evaluation? Specifically, we assess whether they show identical patterns of dependence on two key dimensions of moral evaluation: A person’s intentions, and the outcomes that they cause. We address this issue in a “trembling hand” economic game. In this game, an allocator divides a monetary stake between themselves and a responder based on a stochastic mechanism. This allows for dissociations between the allocator’s intent and the actual outcome. Responders were either given the opportunity to punish or reward the allocator (partner control) or to switch to a different partner for a subsequent round of play (partner choice). Our results suggest that partner control and partner choice behaviors are supported by distinct underlying cognitive processes: Partner control exhibits greater sensitivity to the outcomes a partner causes, while partner choice is influenced almost exclusively by a partner’s intentions. This cognitive dissociation can be understood in light of the unique adaptive functions of partner control and partner choice.     

Chronic Over-Expression of Heat Shock Protein 27 Attenuates Atherogenesis and Enhances Plaque Remodeling: A Combined Histological and Mechanical Assessment of Aortic Lesions

Aims

Expression of Heat Shock Protein-27 (HSP27) is reduced in human coronary atherosclerosis. Over-expression of HSP27 is protective against the early formation of lesions in atherosclerosis-prone apoE^−/− mice (apoE^−/−HSP27^o/e) - however, only in females. We now seek to determine if chronic HSP27 over-expression is protective in a model of advanced atherosclerosis in both male and female apoE^−/− mice.

Methods and Results

After 12 weeks on a high fat diet, serum HSP27 levels rose more than 16-fold in male and female apoE^−/−HSP27^o/e mice, although females had higher levels than males. Relative to apoE^−/− mice, female apoE^−/−HSP27^o/e mice showed reductions in aortic lesion area of 35% for en face and 30% for cross-sectional sinus tissue sections – with the same parameters reduced by 21% and 24% in male cohorts; respectively. Aortic plaques from apoE^−/−HSP27^o/e mice showed almost 50% reductions in the area occupied by cholesterol clefts and free cholesterol, with fewer macrophages and reduced apoptosis but greater intimal smooth muscle cell and collagen content. The analysis of the aortic mechanical properties showed increased vessel stiffness in apoE^−/−HSP27^o/e mice (41% in female, 34% in male) compare to apoE^−/− counterparts.

Conclusions

Chronic over-expression of HSP27 is atheroprotective in both sexes and coincides with reductions in lesion cholesterol accumulation as well as favorable plaque remodeling. These data provide new clues as to how HSP27 may improve not only the composition of atherosclerotic lesions but potentially their stability and resilience to plaque rupture.     

Poly(I:C)/Alum Mixed Adjuvant Priming Enhances HBV Subunit Vaccine-Induced Immunity in Mice When Combined with Recombinant Adenoviral-Based HBV Vaccine Boosting

Background

Virus-specific cellular immune responses play a critical role in virus clearance during acute or chronic HBV infection. Currently, the commercially available HBV vaccine is combined with alum adjuvant, which stimulates mainly Th2 immune responses. Therefore, development of new therapeutic HBV vaccine adjuvants and immune strategies that also promote Th1 and CTL responses is urgently needed.

Methodology/Principal findings

To improve the immunity induced by the novel HBSS1 HBV vaccine, we evaluated the ability of adjuvants, including alum, CpG and polyriboinosinic polyribocytidylic acid [poly(I:C)], to enhance the response when boosted with the recombinant adenoviral vector vaccine rAdSS1. The immune responses to different adjuvant combinations were assessed in C57BL/6 mice by enzyme-linked immunosorbent assay (ELISA), ELISpot and cytokine release assays. Among the combinations tested, a HBV protein particle vaccine with CpG/alum and poly(I:C)/alum priming combinations accelerated specific seroconversion and produced high antibody (anti-PreS1, anti-S antibody) titres with a Th1 bias. After boosting with recombinant adenoviral vector vaccine rAdSS1, both groups produced a strong multi-antigen (S and PreS1)-specific cellular immune response. HBSS1 immunisation with poly(I:C)/alum priming also generated high-level CD4⁺ and CD8⁺ T cell responses in terms of Th1 cytokines (IFN-γand IL-2).

Conclusions

The protein-vaccine HBSS1 with mixed poly(I:C)/alum adjuvant priming, followed by a rAdSS1 vaccine boost, maximises specific antibody and Th1-biased cellular immune responses. This regime might prove useful in the development of HBV therapeutic vaccines. Furthermore, this promising strategy might be applied to vaccines against other persistent infections, such as human immunodeficiency virus and tuberculosis.     

Saffron (Crocus Sativus L.), Combined with Endurance Exercise,Synergistically Enhances BDNF,Serotonin, and NT-3 in Wistar Rats

Background:Evidence indicates that combined approaches based on exercise and nutrition benefit neural development. We aimed to determine the effect of saffron and endurance training on hippocampus neurogenic factors, neurotrophin-3 gene expression in soleus muscle, and short-term memory in Wistar rats.Methods:The study analyzed four groups of ten rats each: control, exercise, saffron, and saffron plus exercise. The rats in the exercise groups were trained on a rodent motor-driven treadmill. All rats were gavage daily with either saffron extract (40 mg/kg) or water. After eight weeks of intervention all rats were evaluated using the novel object recognition (NOR) test. Blood and tissue samples were collected to measure proteins and neurotrophin-3 gene expression.Results:Rats that received saffron treatment combined with exercise had significantly greater brain-derived neurotrophic factor (BDNF) and serotonin in hippocampus compared to the control and saffron-only-treated rats (p< 0.05). Neurotrophin-3 mRNA in soleus muscle was higher in the saffron plus exercise group than rats in the other three groups (p< 0.05). Hippocampus 5-hydroxyindolacetic acid and short-term memory were significantly greater in all the intervention groups than in the control group (p< 0.05).Conclusion:Saffron, combined with endurance exercise, synergistically increased hippocampus BDNF, serotonin, and muscular neurotrophin-3 mRNA in Wistar rats.Key Words: Endurance Exercise, Memory, Hippocampus, Saffron, Neurotransmitter