bluuebunny/crossref_metadata_2025_split huggingface dataset:
Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-Flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain
Authors: Peris-Yague Alba , Kiemes Amanda , Cash Diana , Cotel Marie-Caroline , Singh Nisha , Vernon Anthony C. , Modinos Gemma 
Published: December 2019

AbstractPost-mortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we therefore combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (p<0.01; q<0.01; d = +1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABAAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.
Natural transformation of the filamentous cyanobacterium Phormidium lacuna
Authors: Nies Fabian , Mielke Marion , Pochert Janko , Lamparter Tilman 
Published: December 2019

AbstractResearch for biotechnological applications of cyanobacteria focuses on synthetic pathways and bioreactor design, while little effort is devoted to introduce new, promising organisms in the field. Applications are most often based on recombinant work, and the establishment of transformation can be a risky, time-consuming procedure. In this work we demonstrate the natural transformation of the filamentous cyanobacterium Phormidium lacuna and insertion of a selection marker into the genome by homologous integration. This is the first example for natural transformation of a member of the order Oscillatoriales. We found that Phormidium lacuna is polyploid, each cell has about 20-100 chromosomes. Transformed filaments were resistant against up to 15 mg/ml of kanamycin, and the high resistance feature allowed for rapid segregation into all chromosomes. Formerly, natural transformation in cyanobacteria has been considered a rare and exclusive feature of a few unicellular species. Our finding suggests that natural competence is more distributed among cyanobacteria than previously thought. This is supported by bioinformatic analyses which show that all protein factors for natural transformation are present in the majority of the analyzed cyanobacteria.
Adverse caregiving in infancy blunts neural processing of the mother: Translating across species
Authors: Opendak Maya , Theisen Emma , Blomkvist Anna , Hollis Kaitlin , Lind Teresa , Sarro Emma , Lundström Johan N. , Tottenham Nim , Dozier Mary , Wilson Donald A , Sullivan Regina M 
Published: December 2019

AbstractThe roots of psychopathology frequently take shape during infancy in the context of parent-infant interactions and adversity. Yet, neurobiological mechanisms linking these processes during infancy remain elusive. Here, using responses to attachment figures among infants who experienced adversity as a benchmark, we assessed rat pup cortical Local Field Potentials (LFP) and behaviors exposed to adversity in response to maternal rough and nurturing handling by examining its impact on pup separation-reunion with the mother. We show that during adversity, pup cortical LFP dynamic range decreased during nurturing maternal behaviors, but was minimally impacted by rough handling. During reunion, adversity-experiencing pups showed aberrant interactions with mother and blunted cortical LFP. Blocking pup stress hormone during either adversity or reunion restored typical behavior, LFP power, and cross-frequency coupling. This translational approach suggests adversity-rearing produces a stress-induced aberrant neurobehavioral processing of the mother, which can be used as an early biomarker of later-life pathology.
The Genomic Loci of Specific Human tRNA Genes Exhibit Ageing-Related DNA Hypermethylation
Authors: Acton Richard J. , Yuan Wei , Gao Fei , Xia Yudong , Bourne Emma , Wozniak Eva , Bell Jordana , Lillycrop Karen , Wang Jun , Dennison Elaine , Harvey Nicholas , Mein Charles A. , Spector Tim D. , Hysi Pirro G. , Cooper Cyrus , Bell Christopher G. 
Published: December 2019

AbstractThe epigenome deteriorates with age, potentially impacting on ageing-related disease.Here, we interrogate the DNA methylation state of the genomic loci of human tRNA. Whilst arising from only ~46kb (<0.002% genome), this information transfer machinery is the second most abundant cellular transcript. tRNAs also control metabolic processes known to affect ageing, through core translational and additional regulatory roles.We identified a genomic enrichment for age-related DNA hypermethylation at tRNA loci. Analysis in 4,350 MeDIP-seq peripheral-blood DNA methylomes (16-82 years), classified 44 and 21 hypermethylating specific tRNAs at study- and genome-wide significance, respectively, contrasting with 0 hypomethylating. Validation and replication (450k array & independent targeted Bisuphite-sequencing) supported thehypermethylation of this functional unit. The strongest consistent signals, also independent of major cell-type change, occur in tRNA-iMet-CAT-1-4 and tRNA-Ser-AGA-2-6.This study is this first comprehensive evaluation of the genomic DNA methylation state of human tRNA genes and reveals a discreet hypermethylation with advancing age.
The Role of Central Amygdala Corticotropin-Releasing Factor in Predator Odor Stress-Induced Avoidance Behavior and Escalated Alcohol Drinking in Rats
Authors: Weera Marcus M. , Schreiber Allyson L. , Avegno Elizabeth M. , Gilpin Nicholas W. 
Published: December 2019

ABSTRACTPost-traumatic stress disorder (PTSD) is characterized by avoidance of trauma-associated stimuli and amygdala hyperreactivity, and is highly co-morbid with alcohol use disorder (AUD). Our lab uses a predator odor (bobcat urine) stress model that produces conditioned avoidance of an odor-paired context in a subset of rats, mirroring avoidance symptoms that manifest in some but not all humans exposed to trauma. We previously showed that after predator odor stress, Avoiders exhibit escalated alcohol drinking, higher aversion-resistant operant alcohol responding, hyperalgesia, and greater anxiety-like behavior compared to unstressed Controls. We also showed that systemic antagonism of corticotropin-releasing factor-1 receptors (CRFR1) reduced escalation of alcohol drinking in rats not indexed for avoidance, that corticotropin-releasing factor (CRF) infusions into the central amygdala (CeA) produced conditioned place avoidance in stress-naïve rats, and that intra-CeA infusion of a CRFR1 antagonist reduced hyperalgesia in Avoiders. Here, we show that avoidance behavior is persistent after repeated predator odor exposure and is resistant to extinction. In addition, Avoiders showed lower weight gain than Controls after predator odor re-exposure. In the brain, higher avoidance was correlated with higher number of c-Fos+ cells and CRF immunoreactivity in the CeA. Finally, we show that intra-CeA CRFR1 antagonism reversed post-stress escalation of alcohol drinking and reduced avoidance behavior in Avoiders. Collectively, these findings suggest that elucidation of the mechanisms by which CRFR1-gated CeA circuits regulate avoidance behavior and alcohol drinking may lead to better understanding of the neural mechanisms underlying co-morbid PTSD and AUD.
The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma
Authors: Bhat Kruttika , Saki Mohammad , Vlashi Erina , Cheng Fei , Duhachek-Muggy Sara , Alli Claudia , Yu Garrett , Medina Paul , He Ling , Damoiseaux Robert , Pellegrini Matteo , Zemke Nathan R. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Liau Linda M. , Kornblum Harley I. , Pajonk Frank 
Published: December 2019

AbstractGlioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICsin vivoand prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs.SignificanceGBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.
Effectiveness of topical antibiotics in treating corals affected by Stony Coral Tissue Loss Disease
Authors: Neely K.L. , Macaulay K.A. , Hower E.K. , Dobler M.A. 
Published: December 2019

AbstractSince 2014, Stony Coral Tissue Loss Disease (SCTLD) has led to mass mortality of the majority of hard coral species on the Florida Reef Tract. Following the successful treatment of SCTLD lesions on corals in closed aquaria using water dosed with antibiotics, two pastes were developed as vehicles for direct antibiotic treatments on wild corals. These pastes were tested as placebos and with additions of amoxicillin via topical applications over active SCTLD margins on multiple coral species. The effectiveness of the pastes without antibiotics (placebo treatments) was less than 10%. Adding amoxicillin to both pastes increased effectiveness. For one of the two pastes, which was silicone based with a time-release mechanism for the antibiotics, effectiveness in halting disease lesions reached 86% when amoxicillin was added. Topical antibiotic application is a viable tool for the preservation of priority corals affected by SCTLD.
Elevated rates of positive selection drive the evolution of pestiferousness in the Colorado potato beetle (Leptinotarsa decemlineata, Say)
Authors: Cohen Zachary P. , Brevik Kristian , Chen Yolanda H. , Hawthorne David J. , Weibel Benjamin D. , Schoville Sean D. 
Published: December 2019

AbstractInsect pests are characterized by expansion, preference and performance on agricultural crops, high fecundity and rapid adaptation to control methods, which we collectively refer to as pestiferousness. Which organismal traits and evolutionary processes facilitate certain taxa becoming pests remains an outstanding question for evolutionary biologists. In order to understand these features, we set out to test the relative importance of genomic properties that underlie the rapid evolution of pestiferousness in the emerging pest model: the Colorado potato beetle (CPB),Leptinotarsa decemlineataSay. Within theLeptinotarsagenus, only CPB has risen to pest status on cultivatedSolanum. Using whole genomes from ten closely relatedLeptinotarsaspecies, we reconstructed a high-quality species tree of this genus. Within this phylogenetic framework, we tested the relative importance of four drivers of rapid adaptation: standing genetic variation, gene family expansion and contraction, transposable element variation, and protein evolution. Throughout approximately 20 million years of divergence,Leptinotarsashow little evidence of gene family turnover or transposable element variation contributing to pest evolution. However, there is a clear pattern of pest lineages experiencing greater rates of positive selection on protein coding genes, as well as retaining higher levels of standing genetic variation. We also identify a suite of positively selected genes unique to the Colorado potato beetle that are directly associated with pestiferousness. These genes are involved in xenobiotic detoxification, chemosensation, and hormones linked with pest behavior and physiology.
Conserved Ark1-related kinases control TORC2 signaling
Authors: Alcaide-Gavilán Maria , Banuelos Selene , Lucena Rafael , Kellogg Douglas R. 
Published: December 2019

AbstractIn all orders of life, cell cycle progression is dependent upon cell growth, and the extent of growth required for cell cycle progression is proportional to growth rate. Thus, cells growing rapidly in rich nutrients are substantially larger than slow growing cells. In budding yeast, a conserved signaling network surrounding Tor complex 2 (TORC2) controls growth rate and cell size in response to nutrient availability. Here, a search for new components of the TORC2 network identified a pair of redundant kinase paralogs called Ark1 and Prk1. Previous studies found that Ark/Prk play roles in endocytosis. Here, we show that Ark/Prk are embedded in the TORC2 network, where they appear to influence TORC2 signaling independently of their roles in endocytosis. We also show that reduced endocytosis leads to increased cell size, which indicates that cell size homeostasis requires coordinated control of plasma membrane growth and endocytosis. The discovery that Ark/Prk are embedded in the TORC2 network suggests a model in which TORC2-dependent signals control both plasma membrane growth and endocytosis, which would ensure that the rates of each process are matched to each other and to the availability of nutrients so that cells achieve and maintain an appropriate size.
Anti-PD-1 treatment as a neurotherapy to enhance neuronal excitability, synaptic plasticity and memory
Authors: Zhao Junli , Ji Ru-Rong 
Published: December 2019

ABSTRACTEmerging immunotherapy using anti-PD-1 antibodies have improved survival in cancer patients by immune activation. Here we show that functional PD-1 receptor is present in hippocampal CA1 neurons and loss of PD-1 or local anti-PD-1 treatment with nivolumab enhances neuronal excitability and long-term potentiation in CA1 neurons, leading to enhanced learning and memory. Our findings suggest that anti-PD-1 antibody also acts as a neurotherapy for improving memory and counteracting cognitive decline.
An RNA Degradation Complex Required for Spreading and Epigenetic Inheritance of Heterochromatin
Authors: Shipkovenska Gergana , Durango Alexander , Kalocsay Marian , Gygi Steven P. , Moazed Danesh 
Published: December 2019

AbstractHeterochromatin assembly requires the methylation of histone H3 lysine 9 by the Clr4(Suv39h) methyltransferase and both the spreading and epigenetic inheritance of heterochromatin involve the recognition of H3K9me-containing nucleosomes by Clr4 and catalysis of H3K9me on adjacent nucleosomes. How this read-write mechanism overcomes obstacles posed by RNA polymerase II and nascent RNA in its path is not fully understood. Here we identify a role for the highly conserved and essential Rix1-containing complex (here referred to as the rixosome), with known RNA endonuclease and polynucleotide kinase activities required for ribosomal RNA (rRNA) processing, in spreading and epigenetic inheritance of heterochromatin. Viable mutations in rixosome subunits that disrupt its association with Swi6/HP1 fail to localize to heterochromatin, lead to accumulation of heterochromatic RNAs, and block spreading of H3K9me and silencing away from nucleation sites into actively transcribed regions. These findings reveal a new pathway for degradation of heterochromatic RNAs with essential roles in heterochromatin spreading and inheritance.
Antibiotic degradation by commensal microbes shields pathogens
Authors: Gjonbalaj Mergim , Keith James W. , Do Mytrang , Hohl Tobias M. , Pamer Eric G. , Becattini Simone 
Published: December 2019

AbstractThe complex bacterial populations that constitute the gut microbiota can harbor antibiotic-resistance genes (ARGs), including those encoding for β-lactamase enzymes (BLA), which degrade commonly prescribed antibiotics such as ampicillin. While it is known that ARGs can be transferred between bacterial species, with dramatic public health implications, whether expression of such genes by harmless commensal bacterial species shields antibiotic-sensitive pathogens in trans by destroying antibiotics in the intestinal lumen is unknown. To address this question, we colonized GF mice with a model intestinal commensal strain of E. coli that produces either functional or defective BLA. Mice were subsequently infected with Listeria monocytogenes or Clostridioides difficile followed by treatment with oral ampicillin. Production of functional BLA by commensal E. coli markedly reduced clearance of these pathogens and enhanced systemic dissemination during ampicillin treatment. Pathogen resistance was independent of ARG acquisition via horizontal gene transfer but instead relied on antibiotic degradation in the intestinal lumen by BLA. We conclude that commensal bacteria that have acquired ARGs can mediate shielding of pathogens from the bactericidal effects of antibiotics.
Mitochondrial translation and dynamics synergistically extend lifespan inC. elegansthrough HLH-30
Authors: Liu Yasmine J. , McIntyre Rebecca L. , Janssens Georges E. , Williams Evan G. , Lan Jiayi , van der Veen Henk , van der Wel Nicole N. , Mair William B. , Aebersold Ruedi , MacInnes Alyson W. , Houtkooper Riekelt H. 
Published: December 2019

AbstractMitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan inC. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show inC. elegansthat disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity.SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.
A stomatal model of anatomical tradeoffs between gas exchange and pathogen colonization
Authors: Muir Christopher D. 
Published: December 2019

ABSTRACTStomatal pores control both leaf gas exchange and are one route for infection of internal plant tissues by many foliar pathogens, setting up the potential for tradeoffs between photosynthesis and defense. Anatomical shifts to lower stomatal density and/or size may also limit pathogen colonization, but such developmental changes could permanently reduce the gas exchange capacity for the life of the leaf. I developed and analyzed a spatially explicit model of pathogen colonization on the leaf as a function of stomatal size and density, anatomical traits which partially determine maximum rates of gas exchange. The model predicts greater stomatal size or density increases the probability of colonization, but the effect is most pronounced when the fraction of leaf surface covered by stomata is low. I also derived scaling relationships between stomatal size and density that preserves a given probability of colonization. These scaling relationships set up a potential anatomical conflict between limiting pathogen colonization and minimizing the fraction of leaf surface covered by stomata. Although a connection between gas exchange and pathogen defense has been suggested empirically, this is the first mathematical model connecting gas exchange and pathogen defense via stomatal anatomy. A limitation of the model is that it does not include variation in innate immunity and stomatal closure in response to pathogens. Nevertheless, the model makes predictions that can be tested with experiments and may explain variation in stomatal anatomy among plants. The model is generalizable to many types of pathogens, but lacks significant biological realism that may be needed for precise predictions.