Oncogenic RAS Signalling Promotes Tumour Immunoresistance by Stabilising PD-L1 mRNA

The immunosuppressive molecule PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. Recent clinical trials of immunotherapies in cancer using antibodies targeting PD-L1 and its receptor PD-1 have led to promising responses in a subset of patients. These results emphasise the pressing need for biomarkers of patient response and means to increase the number of patients that benefit from these immunotherapies. One potential biomarker is PD-L1 on tumour cells, although the relative importance of the tumour microenvironment and cellintrinsic signalling in the regulation of PD-L1 expression remains unclear. The use of physiological, genetically engineered mouse models (GEMMs) of human cancer may accelerate the preclinical development of immunotherapies targeting complex cancer-host interactions and improve our understanding of the regulation of PD-L1 in cancer. Here, we discover that widely used, autochthonous GEMMs of Ras-driven lung cancer are poorly immunogenic and refractory to immunotherapies, questioning their disease-relevance and suitability for the preclinical study of immunotherapies in their current form. In addition, we investigate the molecular basis of tumour cell PD-L1 expression in lung cancer. We report that oncogenic RAS signalling is sufficient to upregulate tumour cell PD-L1 expression. Mechanistically, RAS signalling increases PD-L1 mRNA stability by modulating the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3’UTR of PD-L1 mRNA. In human and mouse lung cancer, TTP expression is reduced and its restoration in tumour cells enhances anti-tumour immunity. Our findings have implications for the interpretation of tumour PD-L1 expression as a biomarker for patient response to immunotherapies, and suggest a role for oncogenic RAS signalling in immune evasion

Is sex necessary?

Fungal sexual reproductive modes have markedly high diversity and plasticity, and asexual species have been hypothesized to arise frequently from sexual fungal species. A recent study on the red yeasts provides further support for the notion that sexual ancestors may give rise to shorter-lived asexual species. However, presumed asexual species may also be cryptically sexual, as revealed by other recent studies

Peripheral biomarkers for first-episode psychosis-opportunities from the neuroinflammatory hypothesis of schizophrenia

Objective Schizophrenia is a disabling disorder of unknown aetiology, lacking definite diagnostic method and cure. A reliable biological marker of schizophrenia is highly demanded, for which traceable immune mediators in blood could be promising candidates. We aimed to gather the best findings of neuroinflammatory markers for first-episode psychosis (FEP). Methods We performed an extensive narrative review of online literature on inflammation-related markers found in human FEP patients only. Results Changes to cytokine levels have been increasingly reported in schizophrenia. The peripheral levels of IL-1 (or its receptor antagonist), soluble IL-2 receptor, IL-4, IL-6, IL-8, and TNF-a have been frequently reported as increased in FEP, in a suggestive continuum from high-risk stages for psychosis. Microglia and astrocytes establish the link between this immune signalling and the synthesis of noxious tryptophan catabolism products, that cause structural damage and directly hamper normal neurotransmission. Amongst these, only 3-hydroxykynurenine has been consistently described in the blood of FEP patients. Conclusion Peripheral molecules stemming from brain inflammation might provide insightful biomarkers of schizophrenia, as early as FEP or even prodromal phases, although more timeand clinically-adjusted studies are essential for their validation.This work has been conducted with the support of the Portuguese Foundation for Science and Technology

Deterministic Factors of Stock Networks based on Cross-correlation in Financial Market

The stock market has been known to form homogeneous stock groups with a higher correlation among different stocks according to common economic factors that influence individual stocks. We investigate the role of common economic factors in the market in the formation of stock networks, using the arbitrage pricing model reflecting essential properties of common economic factors. We find that the degree of consistency between real and model stock networks increases as additional common economic factors are incorporated into our model. Furthermore, we find that individual stocks with a large number of links to other stocks in a network are more highly correlated with common economic factors than those with a small number of links. This suggests that common economic factors in the stock market can be understood in terms of deterministic factors.Comment: 4 pages, 1 figur

Insulin glycation by methylglyoxal results in native-like aggregation and inhibition of fibril formation

<p>Abstract</p> <p>Background</p> <p>Insulin is a hormone that regulates blood glucose homeostasis and is a central protein in a medical condition termed insulin injection amyloidosis. It is intimately associated with glycaemia and is vulnerable to glycation by glucose and other highly reactive carbonyls like methylglyoxal, especially in diabetic conditions. Protein glycation is involved in structure and stability changes that impair protein functionality, and is associated with several human diseases, such as diabetes and neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Familiar Amyloidotic Polyneuropathy. In the present work, methylglyoxal was investigated for their effects on the structure, stability and fibril formation of insulin.</p> <p>Results</p> <p>Methylglyoxal was found to induce the formation of insulin native-like aggregates and reduce protein fibrillation by blocking the formation of the seeding <it>nuclei</it>. Equilibrium-unfolding experiments using chaotropic agents showed that glycated insulin has a small conformational stability and a weaker dependence on denaturant concentration (smaller m-value). Our observations suggest that methylglyoxal modification of insulin leads to a less compact and less stable structure that may be associated to an increased protein dynamics.</p> <p>Conclusions</p> <p>We propose that higher dynamics in glycated insulin could prevent the formation of the rigid cross-β core structure found in amyloid fibrils, thereby contributing to the reduction in the ability to form fibrils and to the population of different aggregation pathways like the formation of native-like aggregates.</p

Angular dependence of the bulk nucleation field Hc2 of aligned MgB2 crystallites

The angular dependence of the bulk nucleation field of a sample made of aligned MgB2 crystallites was obtained using dc magnetization and ac susceptibility measurements. A good fitting of the data by the three-dimensional anisotropic Ginzburg-Landau theory attests to the bulk nature of the critical field H-c2. We found a mass anisotropy ratio epsilon2 approximate to0.39 that implies an anisotropy of the Fermi velocity, with a ratio of 1.6 between the in-plane and perpendicular directions, if an isotropic gap energy is assumed. For an s-wave anisotropic gap this ratio could increase to 2.5. Besides the fundamental implications of this result, it also implies the use of texturization techniques to optimize the critical current in wires and other polycrystalline forms of MgB2.641

A thermocatalytic perovskite-graphene oxide nanofiltration membrane for water depollution

A novel nanofiltration membrane, whose active layer consists of 98.6 wt% of a thermocatalytic perovskite with composition Sr0.85Ce0.15FeO3-δ (CSF), 1.0 wt% of graphene oxide (GO), and 0.4 wt% of a humic acid-like (HAL) crosslinker, was deposited over a commercial flat-sheet polyethersulfone support with good reproducibility by a simple 1-step coating procedure. The synergistic coupling of CSF and the crosslinked GO resulted in an improved catalytic activity for bisphenol A (BPA) abatement as a model pollutant. The thermocatalytic CSF/GO/HAL (GOT) membrane was tested in a nanofiltration crossflow apparatus with a model BPA solution and with a real urban wastewater treatment plant effluent. Its performances were compared with those of a HAL crosslinked GO (GOHAL) reference membrane. The GOT membrane presented high rejection towards BPA, antifouling properties, and stability under the filtration conditions. Moreover, when compared to the GOHAL reference, the thermocatalytic GOT membrane was able to reduce the concentration of BPA and the total organic carbon in the feed during filtration. Hence, the GOT membrane appears to have high potential in water treatment due to its multifunctional characteristics, which include molecular sieving, thermocatalytic oxidation of organic pollutants, and self-cleaning properties. Additionally, the membrane material showed no significant toxicity to the aquatic model organisms Raphidocelis subcapitata, Aliivibrio fischeri, and Daphnia magna at concentrations below 50 ppm.Fil: Bortot Coelho, Fabricio E.. Università di Torino; Italia. Liqtech International A/s; DinamarcaFil: Nurisso, Federica. Università di Torino; Italia. Aalborg University; DinamarcaFil: Boffa, Vittorio. Aalborg University; DinamarcaFil: Ma, Xianzheng. Aalborg University; DinamarcaFil: Rasse Suriani, Federico Ariel Osvaldo. Aalborg University; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Roslev, Peter. Aalborg University; DinamarcaFil: Magnacca, Giuliana. Università di Torino; ItaliaFil: Candelario, Victor. Liqtech International A/s; DinamarcaFil: Deganello, Francesca. Istituto Per Lo Studio Dei Materiali Nanostrutturati, Rome; ItaliaFil: La Parola, Valeria. Istituto Per Lo Studio Dei Materiali Nanostrutturati, Rome; Itali