Opinion diversity and community formation in adaptive networks

It is interesting and of significant importance to investigate how network structures co-evolve with opinions. The existing models of such co-evolution typically lead to the final states where network nodes either reach a global consensus or break into separated communities, each of which holding its own community consensus. Such results, however, can hardly explain the richness of real-life observations that opinions are always diversified with no global or even community consensus, and people seldom, if not never, totally cut off themselves from dissenters. In this article, we show that, a simple model integrating consensus formation, link rewiring and opinion change allows complex system dynamics to emerge, driving the system into a dynamic equilibrium with co-existence of diversified opinions. Specifically, similar opinion holders may form into communities yet with no strict community consensus; and rather than being separated into disconnected communities, different communities remain to be interconnected by non-trivial proportion of inter-community links. More importantly, we show that the complex dynamics may lead to different numbers of communities at steady state with a given tolerance between different opinion holders. We construct a framework for theoretically analyzing the co-evolution process. Theoretical analysis and extensive simulation results reveal some useful insights into the complex co-evolution process, including the formation of dynamic equilibrium, the phase transition between different steady states with different numbers of communities, and the dynamics between opinion distribution and network modularity, etc.Comment: 12 pages, 8 figures, Journa

A protein kinase a-independent pathway controlling aquaporin 2 trafficking as a possible cause for the syndrome of inappropriate antidiuresis associated with polycystic kidney disease 1 haploinsufficiency.

Renal water reabsorption is controlled by vasopressin (AVP) which binds to V2 receptors resulting in PKA activation, phosphorylation of AQP2 at serine 256 (pS256) and translocation to the plasma membrane. Besides S256, AVP causes dephosphorylation of S261. Recent studies showed that cyclin-dependent kinases can phosphorylate S261 AQP2 peptides in vitro. In an attempt to investigate the possible role of cdks on AQP2 phosphorylation, we identified a new PKA-independent pathway regulating AQP2 trafficking. In ex-vivo kidney slices and MDCK-AQP2 cells, R-roscovitine, a specific cdks inhibitor, increased pS256 and decreased pS261. The changes in AQP2 phosphorylation were paralleled by an increase in cell surface AQP2 expression and osmotic water permeability in the absence of forskolin stimulation. Of note, R-roscovitine didn’t alter cAMP-dependent PKA activity. Because phosphorylation results from the balance between kinase and phosphatase activity, we evaluated the possible contribution of protein phosphatases PP1, PP2A and PP2B. Of these, R-roscovitine treatment specifically reduced PP2A protein expression and activity in MDCK cells. Interestingly, in PKD1+/- mice displaying a syndrome of inappropriate antidiuresis with high level of pS256 despite unchanged AVP and cAMP, we found a reduced PP2A expression and activity and reduced pS261. Similarly to what previously found in PKD1+/- mice, R-roscovitine treatment caused a significant decrease in intracellular calcium in MDCK cells. Our data indicate that a reduced activity of PP2A, secondary to reduced intracellular Ca2+ levels, promotes AQP2 trafficking independently of the AVP-PKA axis. This pathway may be relevant for explaining pathological states characterized by inappropriate AVP secretion and positive water balance

Verificación de las Curvas de Paschen y la Ley de Peek en microionizadores por descarga luminiscente

En este trabajo analizamos el sistema de ionización por descarga luminiscente para su utilización como fuente de iones en un equipo de identificación de compuestos químicos tipo IMS. Se realizaron modelos de descarga corona implementados con tecnología MEMS (Sistemas Micro-electro Mecánicos). Se propone que en la escala micrométrica es posible mejorar rendimientos, confiabilidad y demandas operativas. Así se redujo la tensión de la fuente de alimentación a menos de 1kV.Centro de Técnicas Analógico-Digitale

Regulatory noncoding and predicted pathogenic coding variants of ccr5 predispose to severe covid-19

Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10−5 ) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5

Reversal of <i>MYB </i>-dependent suppression of <i>MAFB </i>expression overrides leukaemia phenotype in MLL-rearranged AML

Abstract The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias

SLC25A22 is a novel gene for migrating partial seizures in infancy

Objective To identify a genetic cause for migrating partial seizures in infancy (MPSI). Methods We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22. Results In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport. Interpretation We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22. Ann Neurol 2013;74:873-882 © 2013 American Neurological Association

KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth

The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour

Formation of Zn- and Fe-sulfides near hydrothermal vents at the Eastern Lau Spreading Center: implications for sulfide bioavailability to chemoautotrophs

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies