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Most tweeted bioRxiv papers, last 7 days
386 results found. For more information, click each entry to expand.
3 tweets neuroscience
The ability to distinguish between commonplace and unusual sensory events is critical for efficient learning and adaptive behaviour. This has been investigated using oddball designs in which sequences of often-appearing (i.e. expected) stimuli are interspersed with rare (i.e. surprising) deviants. Resulting differences in electrophysiological responses following surprising compared to expected stimuli are known as visual mismatch responses (VMRs). VMRs are thought to index co-occurring contributions of stimulus repetition effects, expectation suppression (that occurs when one’s expectations are fulfilled), and expectation violation (i.e. surprise) responses; however, these different effects have been conflated in existing oddball designs. To better isolate and quantify effects of expectation suppression and surprise, we adapted an oddball design based on Fast Periodic Visual Stimulation (FPVS) that controls for stimulus repetition effects. We recorded electroencephalography (EEG) while participants (N=48) viewed stimulation sequences in which a single face identity was periodically presented at 6 Hz. Critically, one of two different face identities (termed oddballs) appeared as every 7th image throughout the sequence. The presentation probabilities of each oddball image within a sequence varied between 10-90%, such that participants could form expectations about which oddball face identity was more likely to appear within each sequence. We also included ‘expectation neutral’ 50% probability sequences, whereby consistently biased expectations would not be formed for either oddball face identity. We found that VMRs indexed surprise responses, and effects of expectation suppression were absent. That is, ERPs were more negative-going at occipitoparietal electrodes for surprising compared to neutral oddballs, but did not differ between expected and neutral oddballs. Surprising oddball-evoked ERPs were also highly similar across the 10-40% appearance probability conditions. Our findings indicate that VMRs which are not accounted for by repetition effects are best described as an all-or-none surprise response, rather than a minimisation of prediction error responses associated with expectation suppression. Highlights ### Competing Interest Statement The authors have declared no competing interest.
3 tweets evolutionary biology
Intikhab Alam, Nojood Aalismail, Cecilia Martin, Allan Kamau, Francisco J. Guzmán-Vega, Tahira Jamil, Afaque A Momin, Silvia G. Acinas, Josep M. Gasol, Stefan T. Arold, Takashi Gojobori, Susana Agusti, Carlos M. Duarte
Estimates of marine plastic stocks, a major threat to marine life (), are far lower than expected from exponentially-increasing litter inputs, suggesting important loss factors (, ). These may involve microbial degradation, as the plastic-degrading polyethylene terephthalate enzyme (PETase) has been reported in marine microbial communities (). An assessment of 416 metagenomes of planktonic communities across the global ocean identifies 68 oceanic PETase variants (oPETase) that evolved from ancestral enzymes degrading polycyclic aromatic hydrocarbons. Twenty oPETases show predicted efficiencies comparable to those of laboratory-optimized PETases, suggesting strong selective pressures directing the evolution of these enzymes. We found oPETases in 90.1% of samples across all oceans and depths, particularly abundant at 1,000 m depth, with a strong dominance of Pseudomonadales containing putative highly-efficient oPETase variants in the dark ocean. Enzymatic degradation may be removing plastic from the marine environment while providing a carbon source for bathypelagic microbial communities. : #ref-1 : #ref-2 : #ref-3 : #ref-4
3 tweets plant biology
The lipid composition of organelles acts as a landmark to define membrane identity and specify subcellular function. Phosphoinositides are anionic lipids acting in protein sorting and trafficking at the trans -Golgi network (TGN). In animal cells, sphingolipids are known to control the turnover of phosphoinositides through lipid exchange mechanisms at endoplasmic reticulum/TGN contact sites. In this study, we discovered a completely new mechanism acting on sphingolipid-mediated phosphoinositides homeostasis at the TGN in plant cells. We used multi-approaches to show that a reduction of the acyl-chain length of sphingolipid results in increased level of phosphatidylinositol-4-phosphate (PI4P) at the TGN, independently from either lipid exchange induced by sphingolipid synthetic flux, or local PI4P synthesis. Instead, we found that sphingolipids mediate the consumption of PI4P through phosphoinositide-specific phospholipase C (PI-PLC) and this process impacts the sorting of the auxin efflux carrier PIN2 at the TGN. Together, our data identify a new mode of action of sphingolipids in lipid interplay at the TGN during protein sorting. ### Competing Interest Statement The authors have declared no competing interest.
3 tweets microbiology
The NLRP1 inflammasome is a multiprotein complex that is a potent activator of inflammation. Mouse NLRP1B can be activated through proteolytic cleavage by the bacterial Lethal Toxin (LeTx) protease, resulting in degradation of the N-terminal domains of NLRP1B and liberation of the bioactive C-terminal domain, which includes the caspase activation and recruitment domain (CARD). However, a natural pathogen-derived effector that can activate human NLRP1 remains unknown. Here, we use an evolutionary model to identify several proteases from diverse picornaviruses that cleave human NLRP1 within a rapidly evolving region of the protein, leading to host-specific and virus-specific activation of the NLRP1 inflammasome. Our work demonstrates that NLRP1 acts as a "tripwire" to recognize the enzymatic function of a wide range of viral proteases, and suggests that host mimicry of viral polyprotein cleavage sites can be an evolutionary strategy to activate a robust inflammatory immune response. ### Competing Interest Statement The authors have declared no competing interest.
3 tweets genetics
Kelly L Bolton, Ryan N Ptashkin, Teng Gao, Lior Braunstein, Sean M Devlin, Daniel Kelly, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine C. Coombs, Nicole M Caltabellotta, Mike Walsh, Kenneth Offit, Zsofia Stadler, Diana Mandelker, Jessica Schulman, Akshar Patel, John Philip, Elsa Bernard, Gunes Gundem, Juan E Arango, Max Levine, Juan S Medina, Noushin Farnoud, Dominik Glodzik, Sonya Li, Marc E Robson, Choonsik Lee, Paul DP Pharoah, Konrad Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J Gibson, Benjamin L Ebert, Andrew Young, Todd Druley, Koichi Takahasi, Nancy Gillis, Markus Ball, Eric Padron, David M. Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia M Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria E Arcila, Marc Ladanyi, David B Solit, Michael F. Berger, Martin Tallman, Montserrat García-Closas, Nilanjan Chatterjee, Luis A. Diaz, Ross L. Levine, Lindsay M Morton, Ahmet Zehir, Elli Papaemmanuil
Clonal hematopoiesis (CH) is frequent in cancer patients and associated with increased risk of therapy related myeloid neoplasms (tMN). To define the relationship between CH, oncologic therapy, and tMN progression, we studied 24,439 cancer patients. We show that previously treated patients have increased rates of CH, with enrichment of mutations in DNA Damage Response (DDR) genes (TP53, PPM1D, CHEK2). Exposure to radiation, platinum and topoisomerase II inhibitors have the strongest association with CH with evidence of dose dependence and gene treatment interactions. We validate these associations in serial sampling from 525 patients and show that exposure to cytotoxic and radiation therapy imparts a selective advantage specifically in hematopoietic cells with DDR mutations. In patients who progressed to tMN, the clone at CH demarcated the dominant clone at tMN diagnosis. CH mutational features predict risk of therapy related myeloid neoplasm in solid tumor patients with clinical implications for early detection and treatment decisions.
3 tweets bioengineering
Running title : Salt stress effects in conventional and non-conventional yeasts. Abstract : Biotechnology requires efficient microbial cell factories. The budding yeast Saccharomyces cerevisiae is an important cell factory but for a sustainable use of natural resources more diverse cellular attributes are essential. Here, we benchmarked non-conventional yeasts Kluyveromyces marxianus (KM) and Rhodotorula toruloides (RT) against the extensively characterized strains of S. cerevisiae , CEN.PK and W303. We developed a computational method for the characterization of cell/vacuole volumes and observed an inverse relationship between the maximal growth rate and the median cell volume that was responsive to monovalent cations. We found that the supplementation of certain K+ concentrations to CEN.PK cultures containing 1.0 M Na+ increased the specific growth rate by four-fold with a parabolic shift in the median cell/vacuole volumes. The impairment of ethanol and acetate utilization in CEN.PK, acetate in W303, at the higher K+/Na+ concentrations implied an interference in the metabolic pathways required for their consumption. In RT cultures, the supplementation of K+/Na+ induced a trade-off in glucose utilization but alleviated cellular aggregates formation where specified cationic concentrations increased the beta-carotene yield by 60% compared with the reference. Our comparative analysis of cell/vacuole volumes using exponential phase cultures showed that the median volumes decreased the most for KM and the least for RT in response to studied cations. Noteworthy for the implication in aging research using yeasts, the vacuole to cell volume ratio increased with the increase in cell volume for W303 and KM, but not for CEN.PK and RT. Importance : For designing efficient bioprocesses characterization of microbial cell factories in the relevant culture environment is important. The control of cell volume in response to salt stress is crucial for the productivity of microbial cell factories. We developed an open source computational method for the analysis of optical microscopy images that allowed us to quantify changes in cell/vacuole volumes in response to common salts in yeasts. Our study provides a framework for appreciating the role of cellular/organellar volumes in response to changing physiological environment. Our analysis showed that K+/Na+ interactions could be used for improving the cellular fitness of CEN.PK and increasing the productivity of beta-carotene in R. toruloides , which is a commercially important antioxidant and a valuable additive in foods. Key words: Microbial cell factories, Saccharomyces cerevisiae ; Kluyveromyces marxianus ; Rhodotorula toruloides ; yeast; sodium; potassium; salt stress; cationic stress; osmotic stress; oxidative stress; carotenoids; food additives; image analysis; bioprocess; biotechnology ### Competing Interest Statement The authors have declared no competing interest.
3 tweets ecology
Bird ringing is used for a long time for scientific investigation of migration routes and to better understand breeding events as well as population ecological aspects. It is applied as an inexpensive method although the well-known and major disadvantage of bird ringing is the usually low response rate. In the case of rarer species such as the Red-Footed Falcon (RFF), however, this quota could be higher due to the exclusivity and greater attention of observers. Motivated by own field observations of color-ringed RFF south of Brunswick, Germany in 2019 and no clear and comprehensive publication of verified additional recoveries and ringings, we did further research regarding this issue by following methods: 1) Contacting European Bird Ringing Centers and associated projects, 2) Query and comparison of files with the three national German Bird Ringing Stations, 3) Expanded literature research, 4) Evaluating reports in the citizen science platform ornitho.de, 5) Checking websites of ringing projects (in particular satellite tracking programs) and 6) Own observations. Surprisingly, this study revealed 18 recovered RFF ringed in foreign countries (14 Hungary, 3 Italy, 1 Romania (GPS tracked bird)) during migration or post-nuptial pre-migration time. Additionally, 1 RFF that was caught and ringed in Germany was recovered abroad. This result updates and increases the number of recoveries of RFF in Germany compared to the actual published state on the order of 18 (so far none) and on the order of 6 concerning ID-encoded RFF (GPS-bird excluded) compared to documentation state of the three Bird Ringing Centers in Germany (so far 3 at Beringungszentrale [BZ] Hiddensee, 1 at Institut für Vogelforschung [IfV] Heligoland). Our research and evaluation of raw data succeeded to a 100% identification rate of the bird’s origin countries (n=18) while the rate of ID-encoded RFF by color ring codes revealed 58.8% (n=10, GPS-bird excluded). The reported-by-observer response rate was 41.2%. Interesting data of about the phenology, age and origin of the RFF recovered in Germany are presented. Questions and considerations about the recent reporting system of ringed birds and the increased numbers of RFF during the last years in Germany are discussed. ### Competing Interest Statement The authors have declared no competing interest.
3 tweets immunology
Ge Song, Wan-ting He, Sean Callaghan, Fabio Anzanello, Deli Huang, James Ricketts, Jonathan L. Torres, Nathan Beutler, Linghang Peng, Sirena Vargas, Jon Cassell, Mara Parren, Linlin Yang, Caroline Ignacio, Davey M. Smith, James E. Voss, David Nemazee, Andrew B Ward, Thomas Rogers, Dennis R. Burton, Raiees Andrabi
Pre-existing immune responses to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, either induced in natural infection or through vaccination. Such consequences are well established in the influenza and flavivirus fields. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. We compared serum antibody and memory B cell responses to coronavirus spike (S) proteins from pre-pandemic and SARS-CoV-2 convalescent donors using a series of binding and functional assays. We found weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we found stronger evidence of pre-existing cross-reactive memory B cells that were activated on SARS-CoV-2 infection. Monoclonal antibodies (mAbs) isolated from the donors showed varying degrees of cross-reactivity with betacoronaviruses, including SARS and endemic coronaviruses. None of the cross-reactive mAbs were neutralizing except for one that targeted the S2 subunit of the S protein. The results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2. ### Competing Interest Statement R.A., G.S., W.H., T.F.R., and D.R.B. are listed as inventors on pending patent applications describing the SARS-CoV-2 and HCoV-HKU1 cross-reactive antibodies. D.R.B. is a consultant for IAVI. All other authors have no competing interests to declare.
3 tweets microbiology
Clostridioides difficile infection (CDI) remains an urgent global One Health threat. The genetic heterogeneity seen across C. difficile underscores its wide ecological versatility and has driven the significant changes in CDI epidemiology seen in the last 20 years. We analysed an international collection of over 12,000 C. difficile genomes spanning the eight currently defined phylogenetic clades. Through whole-genome average nucleotide identity, pangenomic and Bayesian analyses, we identified major taxonomic incoherence with clear species boundaries for each of the recently described cryptic clades CI-III. The emergence of these three novel genomospecies predates clades C1-5 by millions of years, rewriting the global population structure of C. difficile specifically and taxonomy of the Peptostreptococcaceae in general. These genomospecies all show unique and highly divergent toxin gene architecture, advancing our understanding of the evolution of C. difficile and close relatives. Beyond the taxonomic ramifications, this work impacts the diagnosis of CDI worldwide. ### Competing Interest Statement DWE declares lecture fees from Gilead, outside the submitted work. No other author has a conflict of interest to declare.
3 tweets bioinformatics
Single cell/nucleus RNA sequencing (scRNAseq) is emerging as an essential tool to unravel the phenotypic heterogeneity of cells in complex biological systems. While computational methods for scRNAseq cell type clustering have advanced, the ability to integrate datasets to identify common and novel cell types across experiments remains a challenge. Here, we introduce a cluster-to-cluster cell type matching method - FR-Match - that utilizes supervised feature selection for dimensionality reduction and incorporates shared information among cells to determine whether two cell type clusters share the same underlying multivariate gene expression distribution. FR-Match is benchmarked with existing cell-to-cell and cell-to-cluster cell type matching methods using both simulated and real scRNAseq data. FR-Match proved to be a stringent method that produced fewer erroneous matches of distinct cell subtypes and had the unique ability to identify novel cell phenotypes in new datasets. In silico validation demonstrated that the proposed workflow is the only self-contained algorithm that was robust to increasing numbers of true negatives (i.e. non-represented cell types). FR-Match was applied to two human brain scRNAseq datasets sampled from cortical layer 1 and full thickness middle temporal gyrus. When mapping cell types identified in specimens isolated from these overlapping human brain regions, FR-Match precisely recapitulated the laminar characteristics of matched cell type clusters, reflecting their distinct neuroanatomical distributions. An R package and Shiny application are provided at https://github.com/JCVenterInstitute/FRmatch for users to interactively explore and match scRNAseq cell type clusters with complementary visualization tools. ### Competing Interest Statement The authors have declared no competing interest.
3 tweets genetics
Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key role in a wide range of genomic analyses. We developed a new method, called FastSMC, that enables accurate biobank-scale detection of IBD segments transmitted by common ancestors living up to several hundreds of generations in the past. FastSMC combines a fast heuristic search for IBD segments with accurate coalescent-based likelihood calculations and enables estimating the age of common ancestors transmitting IBD regions. We applied FastSMC to 487,409 phased samples from the UK Biobank and detected the presence of ~214 billion IBD segments transmitted by shared ancestors within the past 1,500 years. We quantified time-dependent shared ancestry within and across 120 postcodes, obtaining a fine-grained picture of genetic relatedness within the past two millennia in the UK. Sharing of common ancestors strongly correlates with geographic distance, enabling the localization of a sample's birth coordinates from genomic data. We sought evidence of recent positive selection by identifying loci with unusually strong shared ancestry within recent millennia and we detected 12 genome-wide significant signals, including 7 novel loci. We found IBD sharing to be highly predictive of the sharing of ultra-rare variants in exome sequencing samples from the UK Biobank. Focusing on loss-of-function variation discovered using exome sequencing, we devised an IBD-based association test and detected 29 associations with 7 blood-related traits, 20 of which were not detected in the exome sequencing study. These results underscore the importance of modelling distant relatedness to reveal subtle population structure, recent evolutionary history, and rare pathogenic variation. ### Competing Interest Statement The authors have declared no competing interest.
3 tweets neuroscience
Poly (ADP-ribose) (PAR) is a negatively charged polymer that is biosynthesized by Poly (ADP-ribose) Polymerase-1 (PARP-1) and regulates various cellular processes. Alpha-synuclein (αSyn) is an intrinsically disordered protein (IDP) that has been directly implicated with driving the onset and progression of Parkinson′s disease (PD). The mechanisms by which αSyn elicits its neurotoxic effects remain unclear. Recent findings indicate that one of the key processes driving PD pathology are oligomeric species of αSyn. Furthermore, it is well established that the main components of Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients are aggregated hyperphosphorylated (S129) forms of αSyn (pαSyn). In this study, we sought to explore how PARP-1 enzymatic product (PAR) drives the conversion of monomeric αSyn into aggregated assemblies. Our studies show that elevated intracellular levels of PAR promote the transition of αSyn into higher molecular weight forms − including oligomers and pαSyn inclusions. Furthermore, quantitative measurements using in situ proximity ligation assays (PLA) on a transgenic murine model of α-synucleinopathy (M83-SNCA*A53T) and post-mortem PD patient samples, reveal that PAR-pαSyn interactions are predominant in pathological states. In addition, we confirm that the interactions between PAR and αSyn involve electrostatic forces between negatively charged PAR and lysine residues on the N-terminal region of αSyn. Altogether, our findings reveal that PAR plays a critical role in the early stages of monomeric αSyn aggregation, thereby attributing to PD pathogenesis. ### Competing Interest Statement The authors have declared no competing interest.
3 tweets cancer biology
The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational profile may also dictate response with some oncogenes (i.e. WNT/β-catenin) known to mediate immuno-suppression. Building on these observations we performed a multi-omic analysis of human cancer correlating the T cell-inflamed gene expression signature with the somatic mutanome and transcriptome for different immune phenotypes, by tumor type and across cancers. Strong correlations were noted between mutations in oncogenes and non-T cell-inflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c and genes with unknown functions. Conversely, we observe many genes associating with the T cell-inflamed phenotype including VHL and PBRM1, among others. Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion broadly active across cancer types including HIF1A and MYC. Novel examples from specific tumors include sonic hedgehog signaling in ovarian cancer or hormone signaling and novel transcription factors across multiple tumors. Using network analysis, somatic and transcriptomic events were integrated, demonstrating that most non-T cell-inflamed tumors are influenced by multiple pathways. Validating these analyses, we observe significant inverse relationships between protein levels and the T cell-inflamed gene signature with examples including NRF2 in lung, ERBB2 in urothelial and choriogonadotropin in cervical cancer. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms. These results nominate molecular targets and drugs potentially available for immediate translation into clinical trials for patients with cancer.
3 tweets cell biology
Mechanotransduction is a process by which cells sense the mechanical properties of their surrounding environment and adapt accordingly to perform cellular functions such as adhesion, migration and differentiation. Integrin-mediated focal adhesions are major sites of mechanotransduction and their connection with the actomyosin network is crucial for mechanosensing as well as the generation and transmission of forces onto the substrate. Despite having emerged as major regulators of cell adhesion and migration, the contribution of microtubules to mechanotransduction still remains elusive. Here, we show that actomyosin-dependent mechanosensing of substrate rigidity controls microtubule acetylation, a tubulin post-translational modification, by promoting the recruitment of the alpha-tubulin acetyl transferase (αTAT1) to focal adhesions. Microtubule acetylation, in turn, promotes GEF-H1 mediated RhoA activation, actomyosin contractility and traction forces. Our results reveal a fundamental crosstalk between microtubules and actin in mechanotransduction, which contributes to mechanosensitive cell adhesion and migration. ### Competing Interest Statement The authors have declared no competing interest.
3 tweets neuroscience
The Bayesian Brain hypothesis, according to which the brain implements statistical algorithms, is one of the leading theoretical frameworks in neuroscience. There are two distinct underlying philosophies: one in which the brain recovers structures that exist in the world from sensory neural activity (decoding), and another in which it represents latent quantities in an internal model (encoding). We argue that an implicit disagreement on this point underlies much of the vigorous debate surrounding the neural implementation of statistical algorithms, in particular the difference between sampling-based and parametric distributional codes. To demonstrate the complementary nature of the two approaches, we have shown mathematically that encoding by sampling can be equivalently interpreted as decoding task variables in a manner consistent with linear probabilistic population codes (PPCs), a popular decoding approach. Ongoing research on the nature of Bayesian inference in the brain will benefit from making their philosophical stance explicit in order to avoid misunderstandings and false dichotomies. ### Competing Interest Statement The authors have declared no competing interest.
2 tweets bioinformatics
Anna Paola Carrieri, Niina Haiminen, Sean Maudsley-Barton, Laura-Jayne Gardiner, Barry Murphy, Andrew Mayes, Sarah Paterson, Sally Grimshaw, Martyn Winn, Cameron Shand, Will Rowe, Stacy Hawkins, Ashley MacGuire-Flanagan, Jane Tazzioli, John Kenny, Laxmi Parida, Michael Hoptroff, Edward O Pyzer-Knapp
Alterations in the human microbiome have been observed in a variety of conditions such has asthma, gingivitis, dermatitis and cancer, and much remains to be learned about the links between the microbiome and human health. The fusion of artificial intelligence with rich microbiome datasets can offer an improved understanding of the microbiome's role in our health. To gain actionable insights it is essential to consider both the predictive power and the transparency of the models by providing explanations for the predictions. We combine the effort of collecting a corpus of leg skin microbiome samples of two healthy cohorts of women with the development of an explainable artificial intelligence (EAI) approach that provides accurate predictions of phenotypes and explanations. The explanations are expressed in terms of variations in the abundance of key microbes that drive the predictions. We predict skin hydration, subject's age, pre/post-menopausal status and smoking status from the leg skin microbiome. The key changes in microbial composition linked to skin hydration can accelerate the development of personalised treatments for healthy skin, while those associated with age may offer insights into the skin aging process. The leg microbiome signatures associated with smoking and menopausal status are consistent with previous findings from oral/respiratory tract microbiomes and vaginal microbiomes respectively. This suggests that easily accessible microbiome samples could be used to investigate health-related phenotypes, offering potential for non-invasive diagnosis and condition monitoring. Our EAI approach sets the stage for new work focused on understanding the complex relationships between microbial communities and phenotypes. Our approach can be applied to predict any conditions from microbiome samples and has the potential to accelerate the development of microbiome-based personalised therapeutics and non-invasive diagnostics. ### Competing Interest Statement The authors were employed by private or academic organizations as described in the author affiliations at the time this work was completed.
2 tweets cancer biology
The tumor suppressive miR-29 family of microRNAs is encoded by two clusters, miR-29b1~a and miR-29b2~c, and is regulated by several oncogenic and tumor suppressive stimuli. Here we investigated whether oncogenic MAPK hyperactivation regulates miR-29 abundance and how this signaling axis impacts melanoma development. Using mouse embryonic fibroblasts and human melanocytes, we found that oncogenic MAPK signaling stimulates p53-independent and p53-dependent transcription of pri-miR-29b1~a and pri-miR-29b2~c, respectively. Expression analyses revealed that while pri-miR-29a~b1 remains elevated, pri-miR-29b2~c levels decrease during melanoma progression. Using a rapid mouse modeling platform, we showed that inactivation of miR-29 in vivo accelerates melanoma development and decreases overall survival. We identified the transcription factor MAFG as a bona fide miR-29 target that has oncogenic potential in melanocytes and is required for growth of melanoma cells. Our findings suggest that MAPK-induced miR-29 contributes to a tumor suppressive barrier by targeting MAFG, which is overcome by attenuation of miR-29b2~c expression. ### Competing Interest Statement The authors have declared no competing interest.
2 tweets molecular biology
Olfactory receptors (ORs) constitute the largest family of G-protein coupled receptors. They are responsible for the perception of odor (olfaction) and also play important roles in other biological processes, including regulation of cell proliferation. Their increasing diagnostic and therapeutic potential, especially for cancer research, requests the ongoing development of methodologies that would allow their robust functional expression in non-olfactory cells, and dynamic analysis of their signaling pathways. To enable realtime detection of OR activity, we use single cell imaging with genetically encoded fluorescent biosensors, Yellow Cameleon or EPAC, which are routinely used for kinetic measurements of Ca2+ or cAMP signaling downstream of various G-protein coupled receptors. We demonstrate that the co-expression of Lucy-Rho tagged variants of ORs together with an accessory protein, RTP1s, in HEK293TN cells is sufficient to detect the activity of a panel of ORs. Using this methodology, we were able to detect both Ca2+ and cAMP signaling downstream of twelve ORs within 2 minutes from the application of odorant.
2 tweets neuroscience
Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hours post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis. In vitro application of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentate gyrus (DG)-without ablating adult neurogenesis-can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permits in vivo 2-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system (CNS) should be carefully evaluated.
2 tweets genetics
Danny E. Miller, Kelley Van Vaerenberghe, Angela Li, Emily K. Grantham, Celeste Cummings, Marilyn Barragan, Rhonda Egidy, Allison R Scott, Kate Hall, Anoja Perera, William D. Gilliland, Justin P. Blumenstiel
Transposable elements (TE) are selfish genetic elements that can cause harmful mutations. In Drosophila , it has been estimated that half of all spontaneous visible marker phenotypes are mutations caused by TE insertions. Because of the harm posed by TEs, eukaryotes have evolved systems of small RNA-based genome defense to limit transposition. However, as in all immune systems, there is a cost of autoimmunity and small RNA-based systems that silence TEs can inadvertently silence genes flanking TE insertions. In a screen for essential meiotic genes in Drosophila melanogaster , a truncated Doc retrotransposon within a neighboring gene was found to trigger the germline silencing of ald , the Drosophila Mps1 homolog, a gene essential for meiosis. A subsequent screen for modifiers of this silencing identified a new insertion of a Hobo DNA transposon in the same neighboring gene. Here we describe how the original Doc insertion triggers flanking piRNA biogenesis and local gene silencing and how the additional Hobo insertion leads to de-silencing by reducing flanking piRNA biogenesis triggered by the original Doc insertion. These results support a model of TE-mediated silencing by piRNA biogenesis in cis that depends on local determinants of transcription. This may explain complex patterns of off-target gene silencing triggered by TEs within populations and in the laboratory. It also provides a mechanism of sign epistasis among TE insertions.
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