412 research outputs found

    Coalitional games with veto players: Myopic and rational behavior

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    This paper studies a noncooperative allocation procedure for coalitional games with veto players. The procedure is similar to the one presented by Dagan et al. (1997) for bankruptcy problems. According to it, a player, the proposer, makes a proposal that the remaining players must accept or reject. We present a model where the proposer can make sequential proposals over n periods. If responders are myopic maximizers (i.e. consider each period in isolation), the only subgame perfect equilibrium outcome is the serial rule of Arin and Feltkamp (2012) regardless of the order of moves. If all players are rational, the serial rule still arises as the unique subgame perfect equilibrium outcome if the order of moves is such that stronger players must respond to the proposal after weaker ones

    \u3cem\u3eTrichodysplasia Spinulosa\u3c/em\u3e-Associated Polyomavirus Uses a Displaced Binding Site on VP1 to Engage Sialylated Glycolipids

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    Trichodysplasia spinulosa-associated Polyomavirus (TSPyV) was isolated from a patient suffering from trichodysplasia spinulosa, a skin disease that can appear in severely immunocompromised patients. While TSPyV is one of the five members of the polyomavirus family that are directly linked to a human disease, details about molecular recognition events, the viral entry pathway, and intracellular trafficking events during TSPyV infection remain unknown. Here we have used a structure-function approach to shed light on the first steps of TSPyV infection. We established by cell binding and pseudovirus infection studies that TSPyV interacts with sialic acids during attachment and/or entry. Subsequently, we solved high-resolution X-ray structures of the major capsid protein VP1 of TSPyV in complex with three different glycans, the branched GM1 glycan, and the linear trisaccharides α2,3- and α2,6-sialyllactose. The terminal sialic acid of all three glycans is engaged in a unique binding site on TSPyV VP1, which is positioned about 18 Å from established sialic acid binding sites of other polyomaviruses. Structure-based mutagenesis of sialic acid-binding residues leads to reduction in cell attachment and pseudovirus infection, demonstrating the physiological relevance of the TSPyV VP1-glycan interaction. Furthermore, treatments of cells with inhibitors of N-, O-linked glycosylation, and glycosphingolipid synthesis suggest that glycolipids play an important role during TSPyV infection. Our findings elucidate the first molecular recognition events of cellular infection with TSPyV and demonstrate that receptor recognition by polyomaviruses is highly variable not only in interactions with sialic acid itself, but also in the location of the binding site

    The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

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    Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC. Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested PCR. HPV immunohistochemistry was performed in a subset of samples. Quantitative PCR was performed to determine the presence and viral load of HPyVs with affinity for the skin (HPyV6, HPyV7, HPyV9, MCPyV, and TSPyV). These data were correlated with previous genetic mutational analysis of H, K and NRAS, NOTCH1/2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1/2. Chromosomal aberrations were profiled using single nucleotide polymorphism (SNP) arrays. Results: Forty-five skin lesions from seven patients treated with single agent vemurafenib in 2012–2013 were analyzed: 12 cSCC, 19 viral warts (VW), 2 actinic keratosis (AK), 5 verrucous keratosis/other squamoproliferative (VK/SP) lesions, one melanocytic lesion and 6 normal skin samples. Significant histologic features of viral infection were seen in 10/12 (83%) cSCC. HPV DNA was detected in 18/19 (95%) VW/SP, 9/12 (75%) cSCC, 4/5 (80%) SP, and 3/6 (50%) normal skin samples and in 1/12 cases assessed by immunohistochemistry. HPyV was co-detected in 22/30 (73%) of samples, usually at low viral load, with MCPyV and HPyV7 the most common. SNP arrays confirmed low levels of chromosomal abnormality and there was no significant correlation between HPV or HPyV detection and individual gene mutations or overall mutational burden. Conclusion: Despite supportive clinicopathologic evidence, the role for HPV and HPyV infection in the pathogenesis of BRAFi-induced squamoproliferative lesions remains uncertain. Synergistic oncogenic mechanisms are plausible although speculative. Nonetheless, with the prospect of a significant increase in the adjuvant use of these drugs, further research is justified and may provide insight into the pathogenesis of other BRAFi-associated malignancies

    Communion by extension : discrepancies between policy and practice

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    The growing practice of Communion by Extension was given formal authorisation by the Church of England General Synod in 2000 with the expectation that it would be used in particular circumstances, including explicitly the rural multi-church benefice. This paper reviews the historical origins of the practice of Communion by Extension and clarifies the intentions of the authorisation given in 2000. Then the intentions of the 2000 authorisation are compared and contrasted with current parochial practice within one English diocese. Considerable divergence is found. Five main themes are identified and discussed: the relationship between worship and mission; the pressures on clerical time; sacramental self-sufficiency; the value given to familiarity; and the choice between reservation and congregationalism

    A bargaining procedure leading to the serial rule in games with veto players

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    This paper studies an allocation procedure for coalitional games with veto players. The procedure is similar to the one presented by Arin and Feltkamp (J Math Econ 43:855-870, 2007), which is based on Dagan et al. (Games Econ Behav 18:55-72, 1997). A distinguished player makes a proposal that the remaining players must accept or reject, and conflict is solved bilaterally between the rejector and the proposer. We allow the proposer to make sequential proposals over several periods. If responders are myopic maximizers (i.e. consider each period in isolation), the only equilibrium outcome is the serial rule of Arin and Feltkamp (Eur J Oper Res 216:208-213, 2012) regardless of the order of moves. If all players are fully rational, the serial rule still arises as the unique subgame perfect equilibrium outcome if the order of moves is such that stronger players respond to the proposal after weaker ones

    Convalescent plasma in a patient with protracted COVID-19 and secondary hypogammaglobulinemia due to chronic lymphocytic leukemia: buying time to develop immunity?

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    It is not exactly clear yet which type of immune response prevails to accomplish viral clearance in coronavirus disease 2019 (COVID-19). Studying a patient with chronic lymphocytic leukemia and hypogammaglobulinemia who suffered from COVID-19 provided insight in the immunological responses after treatment with COVID-19 convalescent plasma (CCP). Treatment consisted of oxygen, repeated glucocorticosteroids and multiple dosages of CCP guided by antibody levels. Retrospectively performed humoral and cellular immunity analysis made clear that not every serological test for COVID-19 is appropriate for follow-up of sufficient neutralizing antibodies after CCP. In retrospect, we think that CCP merely bought time for this patient to develop an adequate cell immune response which led to viral clearance and ultimately clinical recovery.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

    HPV type-specific distribution among family members and linen in households of cutaneous wart patients

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    Background Common and plantar warts are caused by human papillomaviruses (HPV). Mode of transmission of wart HPVs within families is largely unknown. Objective To demonstrate similarity of HPV type(s) among wart cases, family members and household linen. Methods In a cross-sectional study, swabs taken from 123 warts and foreheads of 62 index patients and 157 family members and from 58 kitchen towels and 59 bathroom mats were tested for DNA of 23 cutaneous wart-associated HPV types. Generalized estimating equations (GEE) were used to estimate the chance of detecting the same HPV type as was found in the index patients on the family contacts and on the kitchen towels and bathroom mats. Results HPV1, HPV2, HPV27 and HPV57 were the most prevalent types in the warts of the index patients. Altogether, 60 (42.3%) of the 142 family members without warts had HPV DNA on their foreheads. When HPV1 and HPV2 were found in the warts, these types were also frequently (>50%) found on the foreheads of index patients and their family members, as well as on the kitchen towels and the bathroom mats. HPV27 and HPV57 were less frequently found (<25%) on foreheads and linen. No associations were found for age, sex and site of HPV DNA presence. Conclusion Dissemination of skin wart-causing HPV types, from wart cases to household contacts and linen, such as kitchen towels and bathroom mats, is more likely for HPV1 and HPV2 than for HPV27 and HPV57. The role of towels and bathroom mats in HPV transmission deserves further investigation.Dermatology-oncolog
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