Reputation and cooperation in defence

Surprisingly high levels of within-group cooperation are observed in conflict situations. Ex- periments confirm that external threats lead to higher cooperation. The psychological literature suggests proximate explanations in the form of group processes, but does not explain how these processes can evolve and persist. We provide an ultimate explanation, in which cooperation is rational response to an external threat. We introduce a model in which groups vary in their willing- ness to help each other against external attackers. Attackers infer cooperativeness of groups from members’ behaviour under attack, and may be deterred by a group that bands together against an initial attack. Then, even self-interested individuals may defend each other when threatened in order to deter future attacks. We argue that a group’s reputation is a public good with a natural weakest-link structure. We extend the model to cooperative and altruistic behaviour in general

Reputation and Cooperation in Defence

Surprisingly high levels of within-group cooperation are observed in conflict situations. Ex- periments confirm that external threats lead to higher cooperation. The psychological literature suggests proximate explanations in the form of group processes, but does not explain how these processes can evolve and persist. We provide an ultimate explanation, in which cooperation is a rational response to an external threat. We introduce a model in which groups vary in their willing- ness to help each other against external attackers. Attackers infer cooperativeness of groups from members’ behaviour under attack, and may be deterred by a group that bands together against an initial attack. Then, even self-interested individuals may defend each other when threatened in order to deter future attacks. We argue that a group’s reputation is a public good with a natural weakest-link structure. We extend the model to cooperative and altruistic behaviour in general.cooperation, conflict, defence, signalling

Genetic Improvement of Grapevine: Tailoring Grape Varieties for The Third Millennium - A Review

The remarkable propagative aptitute of grapevine is one of the key factors contributing to its success as a cultivated species and to the spread of the domesticated grapevine, establishing it as one of the most important fruit species worldwide. Today there are some 8 million hectares of vineyards across the world. It is therefore titting that the successful implementation of the powerful technology of gene manipulation in grapevine is to a large extent reliant on this regenerative ability. Currently, several varieties of grapevines have been successfully genetically transformed, largely by employing somatic embryogenesis to generate highly regenerative target material. Especially attractive in the wine industry is the possibility of improving grapevine varieties by the addition of genes that confer usefultraits, such as resistances against biotic and abiotic factors and manipulation of certain metabolic functions. In principle, gene transfer technology allows for the directed manipulation of a specific trait without altering the characteristic nature of the cultivar, permitting the improvement of the traditional cultivars while maintaining their established varietal characteristics. For the most part, targeted traits currently include disease resistance andimproved berry quality. The promise of this technology is threatened by worldwide resistance to genetically modified organisms, and in the wine industry by complications surrounding the property rights and naming of transgenic vines. If it is not possible to maintain the varietal name when a transgenic vine has the same properties as the original well known variety, the significant advantages of gene technology over traditional breeding programmes are to a large extent lost. If these and other complications can be overcome, the integration of this powerful technology with traditional breeding programmes, and with other initiatives such as the study of the grapevine genome, will ensure a new era in the cultivation of this ancient species

Asp-120 Locates Zn2 for Optimal Metallo-β-lactamase Activity

Metallo-β-lactamases are zinc-dependent hydrolases that inactivate β-lactam antibiotics, rendering bacteria resistant to them. Asp-120 is fully conserved in all metallo-β-lactamases and is central to catalysis. Several roles have been proposed for Asp-120, but so far there is no agreed consensus. We generated four site-specifically substituted variants of the enzyme BcII from Bacillus cereus as follows: D120N, D120E, D120Q, and D120S. Replacement of Asp-120 by other residues with very different metal ligating capabilities severely impairs the lactamase activity without abolishing metal binding to the mutated site. A kinetic study of these mutants indicates that Asp-120 is not the proton donor, nor does it play an essential role in nucleophilic activation. Spectroscopic and crystallographic analysis of D120S BcII, the least active mutant bearing the weakest metal ligand in the series, reveals that this enzyme is able to accommodate a dinuclear center and that perturbations in the active site are limited to the Zn2 site. It is proposed that the role of Asp-120 is to act as a strong Zn2 ligand, locating this ion optimally for substrate binding, stabilization of the development of a partial negative charge in the β-lactam nitrogen, and protonation of this atom by a zinc-bound water molecule

Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade

Greater understanding of tumour immunobiology has led to a new era of cancer treatment in which immuno-oncology (IO) therapies are used to boost anti-cancer immune responses. Prominent among these therapies are immune checkpoint inhibitors (ICIs), antibody-based drugs that can unleash the power of tumour-specific CD8 + T-cells. ICIs targeting the Programmed cell death protein 1 (PD-1) cell surface receptor or its ligand PD-L1 are particularly effective, with clinical studies reporting powerful and durable therapeutic impact against many cancer types, including melanoma and non-small cell lung cancer. ICIs have the potential to transform the landscape of cancer treatment, and their development was recognised by the award of the 2018 Nobel Prize in Physiology or Medicine to James Allison and Tasuku Honjo. However, the proportion of patients responding to anti-PD-1/PD-L1 monotherapy can be low. The next major challenge involves understanding and overcoming the innate and acquired resistance that prevents most patients from responding to PD-1/PD-L1 blockade. In this review, we outline the physiological function of PD-1 and its exploitation by developing tumours. We give an overview of current FDA-approved drugs targeting PD-1 or PD-L1 and summarise clinical progress so far. We then discuss key mechanisms thought to underpin resistance to PD-1/PD-L1 blockade, describing biomarkers that could allow patient responses to be predicted before treatment, and tracked once treatment has started. We also present clinical and pre-clinical combination therapies that have been developed to overcome resistance and which have the potential to substantially extend the therapeutic reach of these revolutionary drugs

Dendritic-Cell (DC)-Based Immunotherapy: Tumor Endothelial Marker 8 (TEM8) Gene Expression of DC Vaccines Correlates with Clinical Outcome

ABSTRACT\ud Previous studies have shown that tumor-endothelial markers (TEMs) are upregulated in immunosuppressive, pro-angiogenic dendritic cells (DCs) found in tumor microenvironments. \ud We reported that pro-angiogenic monocyte-derived DCs (Mo-DCs), utilized for therapeutic vaccination of cancer patients upon maturation, markedly differ in their ability to up-regulate tumor-endothelial marker 8 (TEM8) gene\ud expression. A DC vaccination trial of 17 advanced cancer patients (13 melanoma and 4 renal cell carcinoma), carried out at the Cancer Institute of Romagna (I.R.S.T.) in Meldola, highlighted a significant correlation between delayed-type hypersensitivity test (DTH) and overall survival (OS). In the study, relative TEM8 mRNA and protein expression levels (mature (m) vs. immature (i) DCs), in DCs obtained for therapeutic vaccines were evaluated by quantitative real-time RT-PCR and cytofluorimetric analysis, respectively. mDCs from six healthy donors were included for comparison purposes. Eight non-progressing patients, all DTH-positive, had a mean fold increase\ud (mfi) of 1.97 in TEM8 expression. Similarly, a TEM8 mRNA mfi = 2.7 was found in healthy donor mDCs. Conversely, mDCs from nine progressing patients, all but one with negative DTH, had a TEM8 mRNA mfi of 12.88. Thus, mDC TEM8 expression levels would seem to identify (p = 0.0018) patients who could benefit from DC therapeutic vaccination