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In this article we study the social dynamic of temporal partitioning congestion games (TPGs), in which participants must coordinate an optimal time-partitioning for using a limited resource. The challenge in TPGs lies in determining whether users can optimally self-organize their usage patterns. Reaching an optimal solution may be undermined, however, by a collectively destructive meta-reasoning pattern, trapping users in a socially vicious oscillatory behavior. TPGs constitute a dilemma for both human and animal communities. We developed a model capturing the dynamics of these games and ran simulations to assess its behavior, based on a 2×2 framework that distinguishes between the players' knowledge of other players' choices and whether they use a learning mechanism. We found that the only way in which an oscillatory dynamic can be thwarted is by adding learning, which leads to weak convergence in the no-information condition and to strong convergence in the with-information condition. We corroborated the validity of our model using real data from a study of bats' behaviour in an environment of water scarcity. We conclude by examining the merits of a complexity-based, agent-based modelling approach over a game-theoretic one, contending that it offers superior insights into the temporal dynamics of TPGs. We also briefly discuss the policy implications of our findings.

In this article we study the social dynamic of temporal partitioning congestion games (TPGs), in which participants must coordinate an optimal time-partitioning for using a limited resource. The challenge in TPGs lies in determining whether users can optimally self-organize their usage patterns. Reaching an optimal solution may be undermined, however, by a collectively destructive meta-reasoning pattern, trapping users in a socially vicious oscillatory behavior. TPGs constitute a dilemma for both human and animal communities. We developed a model capturing the dynamics of these games and ran simulations to assess its behavior, based on a 2×2 framework that distinguishes between the players' knowledge of other players' choices and whether they use a learning mechanism. We found that the only way in which an oscillatory dynamic can be thwarted is by adding learning, which leads to weak convergence in the no-information condition and to strong convergence in the with-information condition. We corroborated the validity of our model using real data from a study of bats' behaviour in an environment of water scarcity. We conclude by examining the merits of a complexity-based, agent-based modelling approach over a game-theoretic one, contending that it offers superior insights into the temporal dynamics of TPGs. We also briefly discuss the policy implications of our findings. [ABSTRACT FROM AUTHOR]

The earth's geomagnetic field (GMF) is known to influence the behaviour of a wide range of species, but remains one of the most enigmatic of animal senses. Animals are known to utilize the GMF for a wide range of survival capabilities such as navigation and orienteering, migration, territoriality, homing, etc. Despite a lot of study in this regard on vertebrates, little is known about the effects of GMF on felids. Hence, we analyzed the body alignment of the Indian Leopard during defecation, and walking along the trails in the Jhalana Reserve Forest in India. Using circular statistics, we found that the leopards aligned their bodies on the north-south axis during defecation (mean azimuth -176.4°), while no such preference was found when walking (mean azimuth 52.9°). Thus we prove that leopards are sensitive to the GMF during basic physiological activities and in this context show similar behaviour to other vertebrates studied to date.

Octopus laqueus is a small tropical octopus found in Okinawa, Japan and the greater Indo-Pacific. Octopus are often viewed as solitary animals but O. laqueus live in close proximity in the wild, and will potentially encounter one another on a regular basis, raising the possibility of social tolerance. Adopting shared den occupancy in aquaria as a potential measure of social tolerance in O. laqueus, we studied the animals' preference for shared dens over solitude. We characterized dependence of sharing preference on sex, den availability and den occupancy density. We designed two simple social tolerance assays in aquaria with a total of 45 daily measurements: (i) Pots Equal, with equal numbers of octopuses and dens and (ii) Pots Limited, with a 3:1 ratio of octopuses to dens. We found that O. laqueus will socially tolerate other individuals by sharing tanks and dens and with typically no loss to cannibalism or escape. However, animals also exhibit significant levels of social repulsion, and individuals often chose a solitary den when given the option. The patterns of den occupancy are observed to be consistent with a maximum entropy model that balances seeking shelter against avoiding other animals. The model accurately captures and predicts the data and can be generalized to other organisms and their social interactions. Overall, in O. laqueus the preference for a den is stronger than the preference to be solitary. The animals are tolerant of others with a mixture of sizes in the tank and even in a den, a reported first for octopuses outside mating. The relaxed disposition and social tolerance of O. laqueus make it a promising species to work with in the lab to explore social and potentially other behaviors in octopuses.

The miniaturization of stone tools, as reflected through the systematic production of bladelets and bladelet tools (microliths), characterized many industries of the Late Pleistocene, with the Levantine Epipalaeolithic serving as a well-studied example. It is commonly held that microliths were used as modular inserts in composite projectiles, while their incorporation in other tools for different tasks is generally overlooked, the latter aspect being the main focus of this paper. We present here a more inclusive approach through a case study of the Geometric Kebaran (Middle Epipalaeolithic, ca. 18,500-15,000 cal BP) site of Neve David, Mount Carmel, Israel. Recent excavations at the site exposed a variety of features, and one well-preserved shallow pit provided a large lithic assemblage with ca. 90 microliths. We studied this assemblage using both the low- and high- magnification use-wear protocols, accompanied by a range of experiments. Our results show that a) the fragmentation rate is very high in this assemblage (ca. 90%), b) most of the microliths have identifiable use-wear, c) the microliths were commonly used as inserts in composite projectiles, d) many microliths were used for functions not related to weaponry and hunting, such as wood-working, weed harvesting and meat processing. These findings strongly support the suggestion that the small insets, regardless of their specific type (trapeze, rectangle, backed/retouched bladelet), were used in a wide variety of composite tools. We argue that such a versatile approach and flexibility in the use of microliths reflect a technological advantage where a minimal set of microlithic types, produced in large numbers, could provide the required elements for weapons, as well as for a variety of cutting, processing and harvesting tools needed for mundane tasks at a large Middle Epipalaeolithic camp.

Bacillus cereus is a foodborne pathogen causing emesis and diarrhea in those affected. It is assumed that the non-hemolytic enterotoxin (Nhe) plays a key role in B. cereus induced diarrhea. The ability to trace Nhe activity is important for food safety. While assays such as PCR and ELISA exist to detect Nhe, those methods cannot differentiate between active and inactive forms of Nhe. The existing rabbit ileal loop bioassay used to detect Nhe activity is ethically disfavored because it uses live experimental animals. Here we present a custom built low-cost CCD based luminometer and applied it in conjunction with a cell-based assay using Vero cells transduced to express the luciferase enzyme. The activity of Nhe was measured as its ability to inhibit synthesis of luciferase as quantified by reduction of light emission by the luciferase reaction. Emitted light intensity was observed to be inversely proportional to Nhe concentration over a range of 7 ng/ml to 125 ng/ml, with a limit of detection of 7 ng/ml Nhe.

Over the last two decades, much of the recent efforts dedicated to the Levantine Middle Paleolithic has concentrated on the role of open-air sites in the settlement system in the region. Here focus on the site of 'Ein Qashish as a cases study. Located in present-day northern Israel, the area of this site is estimated to have been >1300 m2, of which ca. 670 were excavated. The site is located at the confluence of the Qishon stream with a small tributary running off the eastern flanks of the Mt. Carmel. At the area of this confluence, water channels and alluvial deposits created a dynamic depositional environment. Four Archaeological Units were identified in a 4.5-m thick stratigraphic sequence were dated by Optically Stimulated Luminescence (OSL) to between-71 and 54 ka, and probably shorter time span-~70-~60 ka. Here we present the diverse material culture remains from the site (lithics, including refitted sequences; modified limestone pieces; molluscs; faunal remains) against their changing paleogeographic backdrop. Skeletal evidence suggests that these remains were associated with Neanderthals. The large-scale repeated accumulation of late Middle Paleolithic remains in the same place on the landscape provides a unique opportunity to address questions of occupation duration and intensity in open-air sites. We find that each occupation was of ephemeral nature, yet presents a range of activities, suggesting that the locale has been used as a generalized residential site rather than specialized task-specific ones. This role of 'Ein Qashish did not change through time, suggesting that during the late Middle Paleolithic settlement system in this part of the southern Levant were stable.

Steroid-resistant GvHD is one of the most significant causes of mortality following allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Treatment with mesenchymal stromal cells (MSC) seems to be a promising solution, however the results from clinical studies are still equivocal. Better selection of candidate patients and improving monitoring of patients following MSC administration can increase treatment effectiveness. In order to determine which characteristics can be used to predict a good response and better monitoring of patients, blood samples were taken prior to therapy, one week and one month after therapy, from 26 allogeneic HSCT patients whom contracted GvHD and were treated with MSCs. Samples were examined for differential blood counts, bilirubin levels and cell surface markers. Serum cytokine levels were also measured. We found that the level of lymphocytes, in particular T and NK cells, may predict a good response to therapy. A better response was observed among patients who expressed low levels of IL-6 and IL-22, Th17 related cytokines, prior to therapy. Patients with high levels of bilirubin prior to therapy showed a poorer response. The results of this study may facilitate early prediction of success or failure of the treatment, and subsequently, will improve selection of patients for MSC therapy.

OBJECTIVE:Ezrin and p130Cas are structural proteins with an important role in signaling pathways and have been shown to promote cancer dissemination. We previously reported on overexpression of both ezrin and p130Cas in breast carcinoma effusions compared to primary carcinomas. Since ovarian and breast carcinomas share the ability to disseminate by forming malignant effusions, we sought to study the role of these molecules in ovarian carcinoma (OC). METHODS:OC cell lines were cultured in two different 3-dimensional conditions, on alginate scaffolds and as spheroids, which served as models for solid tumor and malignant effusions, respectively. shRNA was used to reduce protein expression in the cells. The malignant potential was evaluated by chemo-invasion assay, branching capacity on Matrigel and rate of proliferation. Subsequently, clinical specimens of high-grade serous carcinoma effusions, ovarian tumors and solid metastases were analyzed for ezrin and p130Cas expression. RESULTS:Higher ezrin expression was found in cells composing the spheroids compared to their counterparts cultured on alginate scaffold and in clinical samples of malignant effusions compared to solid tumors. In addition, reduced Ezrin expression impaired the invasion ability and the branching capacity of OC cells to a greater extent than reduced p130Cas expression. However, ezrin and p130Cas expression in effusions was unrelated to clinical outcome. CONCLUSIONS:The 3-dimensional cell cultures were found to mimic the different tumor sites and be applicable as a model. The in vitro results concur with the clinical specimen analysis, suggesting that in OC, the role of ezrin in disease progression is more pronounced than that of p130Cas.

BACKGROUND:There is an increased risk of death due to drug toxicity after release from incarceration. The purpose of this study was to describe the timing, rate and circumstances of drug toxicity deaths following release from incarceration. This information can be used to help design potential preventive interventions. METHODS AND FINDINGS:We reviewed coroner's files to identify deaths in adults in Ontario between 2006 and 2013 caused by drug toxicity (n = 6,978) and these records were matched with provincial correctional records to identify individuals who died within one year of being released from incarceration (n = 702). Twenty percent (n = 137) of the 702 deaths occurred within one week of release. The majority (77%, n = 538) of deaths after release involved one or more opioids. Of the deaths involving opioids, intervention by another person may have been possible in 318 cases. CONCLUSIONS:Between 2006 and 2013 in Ontario, one in ten drug toxicity deaths in adults occurred within one year of release from provincial incarceration. These findings may help to inform the implemention and assessment of interventions aimed at reducing drug toxicity deaths following release from incarceration.

Shiga toxin (Stx) is a common virulence factor of all Shiga toxin producing E. coli (STEC) that cause a wide spectrum of disease, including hemorrhagic colitis and hemolytic uremic syndrome (HUS). Although several commercial kits are available for detection of Stx produced by STEC, none of them are capable of recognizing all subtypes of Stxs, which include three subtypes of Stx1 and seven subtypes of Stx2.New monoclonal and polyclonal antibodies against Stx1 and Stx2 were developed. A universal sandwich ELISA capable of detecting all known subtypes of Stx1 and Stx2 was established using a pool of newly developed antibodies. To precisely monitor the sensitivity of the assay for each subtype of Stxs, recombinant toxoids were created and used as standards in ELISAs. Because of the high affinity of the antibodies incorporated, the ELISA assay is highly sensitive with a limit of detection for the different subtypes of Stx1a and Stx2a between 10 and 50 pg/mL in phosphate buffered saline (PBS). The assay was also able to identify STEC based on the production of Stxs using the supernatants of culture fluids or even single colonies on agar plates without lengthy enrichment in liquid medium. When applied to ground beef samples, this newly developed ELISA was capable of distinguishing beef samples spiked with a single bacterial cell.A highly sensitive and universal assay for all subtypes of Stx1 and Stx2 was developed. It has significantly improved upon the current technologies by avoiding false negative results due to the narrow detection range of the assay. The assay developed in this study can be useful for prompt detection of new and emerging serotypes and screening ground beef samples for contamination of STEC at an early stage in the food supply chain, thus avoiding the need for possible recall.

Many animals copy the choices of others but the functional and mechanistic explanations for copying are still not fully resolved. We relied on novel behavioral protocols to quantify the value of patch-choice copying in fruit flies. In a titration experiment, we quantified how much nutritional value females were willing to trade for laying eggs on patches already occupied by larvae (social patches). Females were highly sensitive to nutritional quality, which was positively associated with their offspring success. Females, however, perceived social, low-nutrition patches (33% of the nutrients) as equally valuable as non-social, high-nutrition ones (100% of the nutrients). In follow-up experiments, we could not, however, either find informational benefits from copying others or detect what females' offspring may gain from developing with older larvae. Because patch-choice copying in fruit flies is a robust phenomenon in spite of potential costs due to competition, we suggest that it is beneficial in natural settings, where fruit flies encounter complex dynamics of microbial communities, which include, in addition to the preferred yeast species they feed on, numerous harmful fungi and bacteria. We suggest that microbial ecology underlies many cases of copying in nature.

We quantified the extent and dynamics of social interactions among fruit fly larvae over time. Both a wild-type laboratory population and a recently-caught strain of larvae spontaneously formed social foraging groups. Levels of aggregation initially increased during larval development and then declined with the wandering stage before pupation. We show that larvae aggregated more on hard than soft food, and more at sites where we had previously broken the surface of the food. Groups of larvae initiated burrowing sooner than solitary individuals, indicating that one potential benefit of larval aggregations is an improved ability to dig and burrow into the food substrate. We also show that two closely related species, D. melanogaster and D. simulans, differ in their tendency to aggregate, which may reflect different evolutionary histories. Our protocol for quantifying social behavior in larvae uncovered robust social aggregations in this simple model, which is highly amenable to neurogenetic analyses, and can serve for future research into the mechanisms and evolution of social behavior.

To understand the effects of the interaction between Mycoplasma and cells on the host cellular function, it is important to elucidate the influences of infection of cells with Mycoplasma on nuclear enzymes such as DNA Topoisomerase type I (Topo I). Human Topo I participates in DNA transaction processes and is the target of anti-cancer drugs, the camptothecins (CPTs). Here we investigated the mechanism by which infection of human tumor cells with Mycoplasma fermentans affects the activity and expression of cellular Topo I, and the anti-cancer efficacy of CPT. Human cancer cells were infected or treated with live or sonicated M. fermentans and the activity and expression of Topo I was determined. M. fermentans significantly reduced (by 80%) Topo I activity in the infected/treated tumor cells without affecting the level of Topo I protein. We demonstrate that this reduction in enzyme activity resulted from ADP-ribosylation of the Topo I protein by Poly-ADP-ribose polymerase (PARP-1). In addition, pERK was activated as a result of the induction of the MAPK signal transduction pathway by M. fermentans. Since PARP-1 was shown to be activated by pERK, we concluded that M. fermentans modified the cellular Topo I activity by activation of PARP-I via the induction of the MAPK signal transduction pathway. Moreover, the infection of tumor cells with M. fermentans diminished the inhibitory effect of CPT. The results of this study suggest that modification of Topo I activity by M. fermentans may alter cellular gene expression and the response of tumor cells to Topo I inhibitors, influencing the anti-cancer capacity of Topo I antagonists.

Gene expression in transduced mammalian cells correlates with virus titer, but high doses of vector for gene therapy leads to toxicity in humans and in animals. Changing the optimal tissue culture medium by adding low levels of environmental stressors, such as 1 µM of the fungal toxin aflatoxin B1 (AFB1), 1 ng of the castor bean protein toxin ricin, or 1% reconstituted milk, enhances transcription and increases production of proteins in transduced mammalian cells as demonstrated by production of the following three recombinant proteins: firefly luciferase, β-galactosidase, and green fluorescent protein (GFP). Higher concentrations of the stress-producing substances damage the cells beyond recovery, resulting in inhibited gene expression and cell death. We also evaluated the effect of the stressor substances on the enhanced infectivity of virus. The presented findings extend methods for large-scale transient recombinant protein production in mammalian cells and suggest that it may be possible to reduce the cytotoxicity of the adenovirus by reducing the virus titer without adversely affecting gene expression levels.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) are frequent causes of severe human diseases ranging from diarrhea to hemolytic uremic syndrome. The existing strategy for detection of STEC relies on the unique sorbitol-negative fermentation property of the O157 strains, the most commonly identified serotype has been E. coli O157. It is becoming increasingly evident, however, that numerous non-O157 STEC serotypes also cause outbreaks and severe illnesses. It is necessary to have new methods that are capable of detecting all STEC strains. METHODS AND FINDINGS: Here we describe the development of a sandwich ELISA assay for detecting both O157 and non-O157 STECs by incorporating a novel polyclonal antibody (pAb) against Stx2. The newly established immunoassay was capable of detecting Stx2a spiked in environmental samples with a limit of detection between 10 and 100 pg/mL in soil and between 100 and 500 pg/mL in feces. When applied to 36 bacterial strains isolated from human and environmental samples, this assay detected Stx2 in all strains that were confirmed to be stx2-positive by real-time PCR, demonstrating a 100% sensitivity and specificity. CONCLUSIONS: The sandwich ELISA developed in this study will enable any competent laboratory to identify and characterize Stx2-producing O157 and non-O157 strains in human and environmental samples, resulting in rapid diagnosis and patient care. The results of epitope mapping from this study will be useful for further development of a peptide-based antibody and vaccine.

BACKGROUND: Shiga-like toxin 2 (Stx2) is one of the most important virulence factors in enterohaemorrhagic Escherichia coli (E. coli) strains such as O157H7. Subtypes of Stx2 are diverse with respect to their sequence, toxicity, and distribution. The most diverse Stx2 subtype, Stx2f, is difficult to detect immunologically, but is becoming more frequently associated with human illness. METHODS AND FINDINGS: A purification regimen was developed for the purification of Stx2f involving cation exchange, hydrophobic interaction, anion exchange, and gel filtration. The molecular weight of Stx2f B-subunit was approximately 5 kDa, which appeared significantly smaller than that of Stx2a (6 kDa) on a SDS-PAGE gel, although the size of the A subunit was similar to Stx2a (30 kDa). Stx2f was shown to be active in both cell-free and cell-based assays. The 50% cytotoxic dose in Vero cells was 3.4 or 1.7 pg (depending on the assay conditions), about 3-5 times higher than the archetypical Stx2a, while the activity of Stx2f and Stx2a in a cell-free rabbit reticulocyte system was similar. Stx2f bound to both globotriose-lipopolysaccharide (Gb3-LPS) and globotetraose-LPS (Gb4-LPS, mimics for globotriaosylceramide and globotetraosylceramide, respectively), but its ability to bind Gb4-LPS was much stronger than Stx2a. Stx2f was also much more stable at low pH and high temperature compared to Stx2a, suggesting the toxin itself may survive harsher food preparation practices. CONCLUSIONS: Here, we detail the purification, biochemical properties, and toxicity of Stx2f, from an E. coli strain isolated from a feral pigeon. Information obtained in this study will be valuable for characterizing Stx2f and explaining the differences of Stx2a and Stx2f in host specificity and cytotoxicity.

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Translocations involving the Mixed Lineage Leukemia (MLL) gene generate in-frame fusions of MLL with more than 50 different partner genes (PGs). Common to all MLL translocations is the exchange not only of coding regions, but also of MLL and PG 3'-untranslated regions (3'UTRs). As a result, the MLL-PG fusion is normally highly expressed and considered the main driver of leukemia development, whereas the function of the PG-MLL fusions in leukemic disease is unclear. As 3'UTRs have been recognized as determinant regions for regulation of gene expression, we hypothesized that loss of the MLL 3'UTR could have a role in generating high MLL-PG levels and leukemia development. Here, we first tested the MLL-PG and PG-MLL mRNA levels in different leukemic cells and tumours and uncovered differential expression that indicates strong repression by the MLL-3'UTR. Reporter assays confirmed that the 3'UTR of MLL, but not of its main PGs, harbours a region that imposes a strong gene silencing effect. Gene suppression by the MLL 3'UTR was largely microRNA independent and did not affect mRNA stability, but inhibited transcription. This effect can at least partially be attributed to a tighter interaction of the MLL 3'UTR with RNA polymerase II than PG 3'UTRs, affecting its phosphorylation state. Altogether, our findings indicate that MLL translocations relieve oncogenic MLL-PG fusions from the repressive MLL 3'UTR, contributing to higher activity of these genes and leukaemia development.