Miracle-dz/UniFAR-FTUs huggingface dataset:
Nuclear reprogramming in heterokaryons is rapid, extensive, and bidirectional

An understanding of nuclear reprogramming is fundamental to the use of cells in regenerative medicine. Due to technological obstacles, the time course and extent of reprogramming of cells following fusion has not been assessed to date. Here, we show that hundreds of genes are activated or repressed within hours of fusion of human keratinocytes and mouse muscle cells in heterokaryons, and extensive changes are observed within 4 days. This study was made possible by the development of a broadly applicable approach, species‐specific transcriptome amplification (SSTA), which enables global resolution of transcripts derived from the nuclei of two species, even when the proportions of species‐specific transcripts are highly skewed. Remarkably, either phenotype can be dominant; an excess of primary keratinocytes leads to activation of the keratinocyte program in muscle cells and the converse is true when muscle cells are in excess. We conclude that nuclear reprogramming in heterokaryons is rapid, extensive, bidirectional, and dictated by the balance of regulators contributed by the cell types. — Adam Palermo, Regis Doyonnas, Nidhi Bhutani, Jason Pomerantz, Ozan Alkan, Helen M. Blau. Nuclear reprogramming in heterokaryons is rapid, extensive, and bidirectional. FASEB J. 23, 1431–1440 (2009)
Joint Dynamic Pricing and Radio Resource Allocation Framework for IoT Services

In this paper, we study the problem of resource allocation as well as pricing in the context of Internet of things (IoT) networks. We provide a novel pricing model for IoT services where all the parties involved in the communication scenario as well as their revenue and cost are determined. We formulate the resource allocation in the considered model as a multi-objective optimization problem where in addition to the resource allocation variables, the price values are also optimization variables. To solve the proposed multi-objective optimization problem, we use the scalarization method which gives different Pareto optimal solutions. We solve the resulting problems using the alternating approach based on the successive convex approximation (SCA) method which converges to a local solution with few iterations. We also consider a conventional approach where each entity tries to maximize its own revenue independently. Simulation results indicate that by applying the proposed joint framework, we can increase the total revenue compared to the conventional case while providing an almost complete fairness among the players. This is while the conventional approach fails to provide such a fairness.
High-resolution three-dimensional NMR structure of the KRAS proto-oncogene promoter reveals key features of a G-quadruplex involved in transcriptional regulation

Non-canonical base pairing within guanine-rich DNA and RNA sequences can produce G-quartets, whose stacking leads to the formation of a G-quadruplex (G4). G4s can coexist with canonical duplex DNA in the human genome and have been suggested to suppress gene transcription, and much attention has therefore focused on studying G4s in promotor regions of disease-related genes. For example, the human KRAS proto-oncogene contains a nuclease-hypersensitive element located upstream of the major transcription start site. The KRAS nuclease-hypersensitive element (NHE) region contains a G-rich element (22RT; 5′-AGGGCGGTGTGGGAATAGGGAA-3′) and encompasses a Myc-associated zinc finger-binding site that regulates KRAS transcription. The NEH region therefore has been proposed as a target for new drugs that control KRAS transcription, which requires detailed knowledge of the NHE structure. In this study, we report a high-resolution NMR structure of the G-rich element within the KRAS NHE. We found that the G-rich element forms a parallel structure with three G-quartets connected by a four-nucleotide loop and two short one-nucleotide double-chain reversal loops. In addition, a thymine bulge is found between G8 and G9. The loops of different lengths and the presence of a bulge between the G-quartets are structural elements that potentially can be targeted by small chemical ligands that would further stabilize the structure and interfere or block transcriptional regulators such as Myc-associated zinc finger from accessing their binding sites on the KRAS promoter. In conclusion, our work suggests a possible new route for the development of anticancer agents that could suppress KRAS expression.
Kinases required in hepatitis C virus entry and replication highlighted by small interference RNA screening

The entry pathway of the hepatitis C virus (HCV), a major human pathogen, into the cell is incompletely defined. To better characterize this viral life cycle stage, we screened a small interfering RNA library dedicated to the membrane trafficking and remodeling with the infection model of Huh‐7.5. 1 cells by HCV pseudoparticles (HCVpp). Results showed that the down‐regulation of different factors implied in clathrin‐mediated endocytosis (CME) inhibits HCVpp cell infection. In addition, knockdown of the phosphatidylinositol 4‐kinase type III‐α (PI4KIIIα) prevented infection by HCVpp or by cell‐culture grown JFH‐1‐based HCV. Moreover, the replication activity of an HCV replicon was also affected by the PI4KIIIα knockdown. Additional investigations on the different members of the PI4K family revealed that the presence of PI4KIIIβ in the host cells influenced their susceptibility to HCVpp infection and their capacity to sustain the HCV replication. The PI4KIII involvement during the HCV life cycle seemed to occur by other ways than the control of the CME or of the membranous expression of HCV receptors. Finally, our library screening completed data on the CME‐dependant entry route of HCV and identified 2 kinases, PI4KIIIα and β,as relevant potential therapeutic targets. —Trotard, M. , Lepère‐Douard, C. , Régeard, M. , Piquet‐Pellorce, C. , Lavillette, D. , Cosset, F. ‐L. , Gripon, P., Le Seyec, J. Kinases required in hepatitis C virus entry and replication highlighted by small interference RNA screening. FASEBJ. 23, 3780–3789 (2009). www.fasebj. org
RNF11 sequestration of the E3 ligase SMURF2 on membranes antagonizes SMAD7 down-regulation of transforming growth factor β signaling

The activity of the E3 ligase, SMURF2, is antagonized by an intramolecular, autoinhibitory interaction between its C2 and Hect domains. Relief of SMURF2 autoinhibition is induced by TGFβ and is mediated by the inhibitory SMAD, SMAD7. In a proteomic screen for endomembrane interactants of the RING-domain E3 ligase, RNF11, we identified SMURF2, among a cohort of Hect E3 ligases previously implicated in TGFβ signaling. Reconstitution of the SMURF2·RNF11 complex in vitro unexpectedly revealed robust SMURF2 E3 ligase activity, with biochemical properties previously restricted to the SMURF2·SMAD7 complex. Using in vitro binding assays, we find that RNF11 can directly compete with SMAD7 for SMURF2 and that binding is mutually exclusive and dependent on a proline-rich domain. Moreover, we found that co-expression of RNF11 and SMURF2 dramatically reduced SMURF2 ubiquitylation in the cell. This effect is strictly dependent on complex formation and sorting determinants that regulate the association of RNF11 with membranes. RNF11 is overexpressed in certain tumors, and, importantly, we found that depletion of this protein down-regulated gene expression of several TGFβ-responsive genes, dampened cell proliferation, and dramatically reduced cell migration in response to TGFβ. Our data suggest for the first time that the choice of binding partners for SMURF2 can sustain or repress TGFβ signaling, and RNF11 may promote TGFβ-induced cell migration.
Insect P450s: mounted for battle in their war against toxins

Transcriptome profiling methods are rapidly changing the ways in which insect responses to the environment can be assessed. One article featured in this issue of Molecular Ecology utilizes global expression analysis to extend previous studies examining the basis of insecticide resistance in Helicoverpa species that are devastating crop pests worldwide. In this issue Tao et al. (2012) have used a wide spectrum of biochemical and molecular techniques to examine the extent to which naturally occurring plant compounds and one synthetic insecticide change transcriptome profiles of Helicoverpa armigera larvae ( Fig. 1 ) to enhance their adaptation to plant toxins and insecticides in their diet and environment. With their data highlighting an array of P450 transcripts and a few esterase transcripts that are correlated with increased tolerance to the insecticide deltamethrin, these researchers provide the first comprehensive evaluation of cytochrome P450 monooxygenase (P450), glutathione S‐transferase (GST) and esterase (Est) gene responses in a lepidopteran species repeatedly subjected to pyrethroid selection. Building on this information, these researchers venture into the realm of the biorational in showing that RNAi‐mediated destruction of one prominent toxin‐inducible P450 transcript can increase sensitivity to deltamethrin, thereby compromising larval growth in the presence of this insecticide. The fact that the resulting levels of deltamethrin tolerance in the RNAi‐silenced larvae are not restored completely to the levels in larvae whose defences are not stimulated by consuming plant compounds provides further evidence that their adaptive strategies for survival in toxin‐rich environments include many different P450, esterase and, possibly, other genes. Together, their data highlight the complexity of the defence systems evolving in lepidopterans and other insect pests.
Mitochondrial genomes reveal the global phylogeography and dispersal routes of the migratory locust

The migratory locust, Locusta migratoria, is the most widely distributed grasshopper species in the world. However, its global genetic structure and phylogeographic relationships have not been investigated. In this study, we explored the worldwide genetic structure and phylogeography of the locust populations based on the sequence information of 65 complete mitochondrial genomes and three mitochondrial genes of 263 individuals from 53 sampling sites. Although this locust can migrate over long distances, our results revealed high genetic differentiation among the geographic populations. The populations can be divided into two different lineages: the Northern lineage, which includes individuals from the temperate regions of the Eurasian continent, and the Southern lineage, which includes individuals from Africa, southern Europe, the Arabian region, India, southern China, South‐east Asia and Australia. An analysis of population genetic diversity indicated that the locust species originated from Africa. Ancestral populations likely separated into Northern and Southern lineages 895 000 years ago by vicariance events associated with Pleistocene glaciations. These two lineages evolved in allopatry and occupied their current distributions in the world via distinct southern and northern dispersal routes. Genetic differences, caused by the long‐term independent diversification of the two lineages, along with other factors, such as geographic barriers and temperature limitations, may play important roles in maintaining the present phylogeographic patterns. Our phylogeographic evidence challenged the long‐held view of multiple subspecies in the locust species and tentatively divided it into two subspecies, L. m. migratoria and L. m. migratorioides.
Flexible-body motions of calmodulin and the farnesylated hypervariable region yield a high-affinity interaction enabling K-Ras4B membrane extraction

In calmodulin (CaM)-rich environments, oncogenic KRAS plays a critical role in adenocarcinomas by promoting PI3K/Akt signaling. We previously proposed that at elevated calcium levels in cancer, CaM recruits PI3Kα to the membrane and extracts K-Ras4B from the membrane, organizing a K-Ras4B–CaM–PI3Kα ternary complex. CaM can thereby replace a missing receptor-tyrosine kinase signal to fully activate PI3Kα. Recent experimental data show that CaM selectively promotes K-Ras signaling but not of N-Ras or H-Ras. How CaM specifically targets K-Ras and how it extracts it from the membrane in KRAS-driven cancer is unclear. Obtaining detailed structural information for a CaM–K-Ras complex is still challenging. Here, using molecular dynamics simulations and fluorescence experiments, we observed that CaM preferentially binds unfolded K-Ras4B hypervariable regions (HVRs) and not α-helical HVRs. The interaction involved all three CaM domains including the central linker and both lobes. CaM specifically targeted the highly polybasic anchor region of the K-Ras4B HVR that stably wraps around CaM's acidic linker. The docking of the farnesyl group to the hydrophobic pockets located at both CaM lobes further enhanced CaM–HVR complex stability. Both CaM and K-Ras4B HVR are highly flexible molecules, suggesting that their interactions permit highly dynamic flexible-body motions. We, therefore, anticipate that the flexible-body interaction is required to extract K-Ras4B from the membrane, as conformational plasticity enables CaM to orient efficiently to the polybasic HVR anchor, which is partially diffused into the liquid-phase membrane. Our structural model of the CaM–K-Ras4B HVR association provides plausible clues to CaM's regulatory action in PI3Kα activation involving the ternary complex in cell proliferation signaling by oncogenic K-Ras.
Clinical Investigation : Central Nervous System Tumor Local Recurrence After Uveal Melanoma Proton Beam Therapy : Recurrence Types and Prognostic Consequences

Local Recurrence After Uveal Melanoma Proton Beam Therapy: Recurrence Types and Prognostic Consequences Jean-Pierre Caujolle, MD,* Vincent Paoli, MD,* Emmanuel Chamorey, PharmD,y,z Celia Maschi, MD,* Stéphanie Baillif, MD,* Joël Herault, PhD,y Pierre Gastaud, MD,* and Jean Michel Hannoun-Levi, MDy *Department of Ophthalmology, Saint Roch Hospital, Nice Teaching Hospital, Nice, France; yDepartment of Radiation Oncology, Protontherapy Center, Centre Antoine Lacassagne, Nice, France; zDepartment of Biostatistics and Epidemiology, Centre Antoine Lacassagne, Nice, France
CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability

Cytotoxic CD8+ T cells are increasingly recognized as key players in various inflammatory and degenerative central nervous system (CNS) disorders. CD8+ T cells are believed to actively contribute to neural damage in these CNS conditions. Conceptually, one can separate two possible ways that CD8+ T cells harm neuronal function or integrity: CD8+ T cells either directly target neurons and their neurites in an antigen‐ or contact‐dependent fashion, or exert their action via “collateral” mechanisms of neuronal damage that might follow destruction of the myelin sheath or glial cells in both the CNS gray and white matter. After introducing clinical examples, in which the putative relevance CD8+ T cells has been demonstrated, we summarize knowledge on the sequence of initiation and execution of CD8+ T‐cell responses in the CNS. This includes the initial antigen cross‐presentation and priming of naive CD8+ T cells, followed by the invasion, migration, and target‐cell recognition of CD8+ effector T cells in the CNS parenchyma. Moreover, we discuss mechanisms of impaired electrical signaling and cell death of neurons as direct and collateral targets of CD8+ T cells in the CNS. —Melzer, N. , Meuth, S. G. , and Wiendl, H. CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability. FASEB J. 23, 3659–3673 (2009). www.fasebj. org
Identification of novel cell migration‐promoting genes by a functional genetic screen

Here we describe the identification of novel cell migration‐promoting genes based on an unbiased functional genetic screen in cultured cells. After the introduction of the retroviral mouse brain cDNA library into NIH3T3 mouse fibroblast cells, migration‐promoted cells were selected by a 3‐dimensional migration assay using cell culture inserts. After 5 rounds of enrichment, cDNAs were retrieved from the cells with a selected phenotype. Cell migration‐promoting activity was confirmed by independent migration assays for the retrieved cDNAs, among which further investigation was focused on coiled‐coil‐helix‐coiled‐coil‐helix domain‐containing protein 2 (chchd2). Whereas overexpression of chchd2 promoted cell migration, knockdown of endogenous chchd2 expression reduced cell migration. Chchd2‐induced cell migration was associated with augmented formation of actin stress fibers and focal adhesion, which was mediated through Akt, RhoA/ROCK, and Jnk pathways. CHCHD2 protein directly interacted with hyaluronic acid‐binding protein 1 (HABP1) that possessed migration‐suppressing activity. Intracellular localization and further functional studies suggested that CHCHD2 and HABP1 may mutually regulate each other to balance cell migration. Thus, chchd2 is a novel cell migration determinant identified by an in vitro functional genetic selection strategy. The selection method can also be useful for the isolation of genes that give other phenotypes of interest. —Seo, M. , Lee, W. ‐H. , Suk, K. Identification of novel cell migration‐promoting genes by a functional genetic screen. FASEB J. 24, 464–478 (2010). www.fasebj. org
All of the human β‐type globin genes compete for LCR enhancer activity in embryonic erythroid cells of yeast artificial chromosome transgenic mice

ABSTRACT In primitive erythroid cells of human β‐globin locus transgenic mice (TgM), the locus control region (LCR)‐proximal ε‐ and γ‐globin genes are transcribed, whereas the distal δ‐ and β‐globin genes are silent. It is generally accepted that the β‐globin gene is competitively suppressed by γ‐globin gene expression at this developmental stage. Previously, however, we observed that ε‐globin gene expression was severely attenuated when its distance from the LCR was extended, implying that β‐globin gene might also be silenced because of its great distance from the LCR. Here, to clarify the β‐globin gene silencing mechanism, we established TgM lines carrying either γ‐ or ε‐ plus γ‐globin promoter deletions, without significantly altering the distance between the β‐globin gene and the LCR. Precocious expression of δ‐ and β‐globin genes was observed in primitive erythroid cells of mutant, but not wild‐type TgM, which was most evident when both the ε and γ promoters were deleted. Thus, we clearly demonstrated that the repression of the δ‐ and β‐globin genes in primitive erythroid cells is dominated by competitive silencing by the ε‐ and γ‐globin gene promoters, and that ε‐ and the other β‐like globin genes might be activated by two distinct mechanisms by the LCR. —Okamura, E. , Matsuzaki, H. , Campbell, A. D. , Engel, J. D. , Fukamizu, A. , Tanimoto, K. All of the human β‐type globin genes compete for LCR enhancer activity in embryonic erythroid cells of yeast artificial chromosome transgenic mice. FASEB J. 23, 4335‐4343 (2009). www.fasebj. org
DNA repair in the extremely radioresistant bacterium Deinococcus radiodurans

Deinococcus radiodurans and other members of the same genus share extraordinary resistance to the lethal and mutagenic effects of ionizing and u.v. radiation and to many other agents that damage DNA. While it is known that this resistance is due to exceedingly efficient DNA repair, the molecular mechanisms responsible remain poorly understood. Following very high exposures to u.v. irradiation (e.g. 500 Jm−2, which is non‐lethal to D. radiodurans), this organism carries out extremely efficient excision repair accomplished by two separate nucleotide excision repair pathways acting simultaneously. One pathway requires the uvrA gene and appears similar to the UvrABC excinuclease pathway defined in Escherichia coli. The other excision repair pathway is specific for u.v. dimeric photoproducts, but is not mediated by a pyrimidine dimer DNA glycosylase. Instead, it is initiated by a second bona fide endonuclease that may recognize both pyrimidine dimers and pyrimidine‐(6–4)pyrimidones. After high doses of ionizing‐radiation (e.g. 1.5Mrad), D. radiodurans can mend >100 double‐strand breaks (dsb) per chromosome without lethality or mutagenesis. Both dsb mending and survival are recA‐dependent, indicating that efficient dsb mending proceeds via homologous recombination. D. radiodurans contains multiple chromosomes per cell, and it is proposed that dsb mending requires extensive recombination amongst these chromosomes, a novel phenomenon in bacteria. Thus, D. radiodurans may serve as an easily accessible model system for the double‐strand‐break‐initiated interchromosomal recombination that occurs in eukaryotic cells during mitosis and meiosis.
Twitter speaks: A case of national disaster situational awareness

In recent years, we have been faced with a series of natural disasters causing a tremendous amount of financial, environmental and human losses. The unpredictable nature of natural disasters behaviour makes it hard to have a comprehensive situational awareness (SA) to support disaster management. Using opinion surveys is a traditional approach to analyse public concerns during natural disasters; however, this approach is limited, expensive and time-consuming. Luckily, the advent of social media has provided scholars with an alternative means of analysing public concerns. Social media enable users (people) to freely communicate their opinions and disperse information regarding current events including natural disasters. This research emphasises the value of social media analysis and proposes an analytical framework: Twitter Situational Awareness (TwiSA). This framework uses text mining methods including sentiment analysis and topic modelling to create a better SA for disaster preparedness, response and recovery. TwiSA has also effectively deployed on a large number of tweets and tracks the negative concerns of people during the 2015 South Carolina flood.