bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mammalian mitochondrial mutational spectrum as a hallmark of cellular and organismal aging
Authors: Mikhaylova A. G. , Mikhailova A. A. , Ushakova K. , Tretiakov E.O. , Shamansky V. , Yurchenko A. , Zazhytska M. , Zdobnov E. , Makeev V. , Yurov V. , Tanaka M. , Gostimskaya I. , Fleischmann Z. , Annis S. , Franco M. , Wasko K. , Kunz W.S , Knorre D.A. , Mazunin I. , Nikolaev S. , Fellay J. , Reymond A. , Khrapko K. , Gunbin K. , Popadin K. 
Published: March 2019

AbstractMutational spectrum of the mitochondrial genome (mtDNA) does not resemble signatures of any known mutagens and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra may be affected by the oxidative damage which is increasing with cellular and organismal aging. However, the well-documented mutational signature of the oxidative damage, G>T substitutions, is typical only for the nuclear genome while it is extremely rare and age-independent in mtDNA. Thus it is still unclear if there is a mitochondria - specific mutational signature of the oxidative damage. Here, reconstructing mtDNA mutational spectra for human cancers originated from 21 tissues with various cell turnover rate, human oocytes fertilized at different ages, and 424 mammalian species with variable generation length which is a proxy for oocyte age, we observed that the frequency of AH>GHsubstitutions (H- heavy chain notation) is positively correlated with cellular and organismal longevity. Moreover, this mutational bias from AHto GHaffects nucleotide content at the fourfold degenerative synonymous positions leading to a deficit of AHand excess of GH, which is especially pronounced in long-lived mammals. Taking into account additionally, that AH>GHis sensitive to time being single stranded during mtDNA asynchronous replication and A>G is associated with oxidative damage of single-stranded DNA in recent bacterial experiments we propose that AH>GHis a mutational signature of oxidative damage in mtDNA.
Identification of PKCα-dependent phosphoproteins in mouse retina
Authors: Wakeham Colin M. , Wilmarth Phillip A. , Cunliffe Jennifer M. , Klimek John E. , Ren Gaoying , David Larry L. , Morgans Catherine W. 
Published: March 2019

AbstractAdjusting to a wide range of light intensities is an essential feature of retinal rod bipolar cell (RBC) function. While persuasive evidence suggests this modulation involves phosphorylation by protein kinase C-alpha (PKCα), the targets of PKCα phosphorylation in the retina have not been identified. PKCα activity and phosphorylation in RBCs was examined by immunofluorescence confocal microscopy using a conformation-specific PKCα antibody and antibodies to phosphorylated PKC motifs. PKCα activity was dependent on light and expression of TRPM1, and RBC dendrites were the primary sites of light-dependent phosphorylation. PKCα-dependent retinal phosphoproteins were identified using a phosphoproteomics approach to compare total protein and phosphopeptide abundance between phorbol ester-treated wild type and PKCα knockout (PKCα-KO) mouse retinas. Phosphopeptide mass spectrometry identified over 1100 phosphopeptides in mouse retina, with 12 displaying significantly greater phosphorylation in WT compared to PKCα-KO samples. The differentially phosphorylated proteins fall into the following functional groups: cytoskeleton/trafficking (4 proteins), ECM/adhesion (2 proteins), signaling (2 proteins), transcriptional regulation (3 proteins), and homeostasis/metabolism (1 protein). Two strongly differentially expressed phosphoproteins, BORG4 and TPBG, were localized to the synaptic layers of the retina, and may play a role in PKCα-dependent modulation of RBC physiology. Data are available via ProteomeXchange with identifier PXD012906.SignificanceRetinal rod bipolar cells (RBCs), the second-order neurons of the mammalian rod visual pathway, are able to modulate their sensitivity to remain functional across a wide range of light intensities, from starlight to daylight. Evidence suggests that this modulation requires the serine/threonine kinase, PKCα, though the specific mechanism by which PKCα modulates RBC physiology is unknown. This study examined PKCα phosophorylation patterns in mouse rod bipolar cells and then used a phosphoproteomics approach to identify PKCα-dependent phosphoproteins in the mouse retina. A small number of retinal proteins showed significant PKCα-dependent phosphorylation, including BORG4 and TPBG, suggesting a potential contribution to PKCα-dependent modulation of RBC physiology.HighlightsPKCα is a major source of phosphorylation in retinal RBC dendrites and its activity in RBCs is light dependent.Proteins showing differential phosphorylation between phorbol ester-treated wild type and PKCα-KO retinas belong to the following major functional groups: cytoskeleton/trafficking (4 proteins), ECM/adhesion (2 proteins), signaling (2 proteins), transcriptional regulation (3 proteins), and homeostasis/metabolism (1 protein).The PKCα-dependent phosphoproteins, BORG4 and TPBG, are present in the synaptic layers of the retina and may be involved in PKCα-dependent modulation of RBC physiology.
A chemical counterpunch:Chromobacterium violaceumATCC31532 produces violacein in response to translation-inhibiting antibiotics
Authors: Lozano Gabriel L. , Guan Changhui , Cao Yanzhuan , Borlee Bradley R. , Broderick Nichole A. , Stabb Eric V. , Handelsman Jo 
Published: March 2019

ABSTRACTBacterially produced antibiotics play important roles in microbial interactions and competition. Antibiosis can induce resistance mechanisms in target organisms and may induce other countermeasures as well. Here, we show that hygromycin A fromStreptomycessp. 2AW inducesChromobacterium violaceumATCC31532 to produce the purple antibiotic violacein. Sublethal doses of other antibiotics that similarly target the polypeptide elongation step of translation likewise induced violacein production, unlike antibiotics with different targets.C. violaceumbiofilm formation and virulence againstDrosophila melanogasterwere also induced by translation-inhibiting antibiotics, and we identified anantibiotic-inducedresponse (air) two-component regulatory system that is required for these responses. Genetic analyses indicated a connection between the Air system, quorum-dependent signaling, and the negative regulator VioS, leading us to propose a model for induction of violacein production. This work suggests a novel mechanism of interspecies interaction in which a bacterium produces an antibiotic in response to inhibition by another bacterium.
Cortical changes associated with parenthood are present in late life
Authors: Orchard Edwina R , Ward Phillip GD , Sforazzini Francesco , Storey Elsdon , Egan Gary F , Jamadar Sharna D 
Published: March 2019

AbstractEarly parenthood results in changes in cortical thickness in regions related to parental care. However, the enduring effects of this period on the structure of the human brain, and cognition in late-life, is unknown. In an elderly sample, we examined the relationship between the number of children parented (here, 1-6 children) and cortical thickness in 267 males (74.0 ±3.5 years) and 231 females (73.8±3.5 years). We also compared cognition and cortical thickness between parents of one child and non-parents, in n=36 males (73.4±3.7 years), and n=46 females (72.8±3.3 years). We obtained a positive relationship between number of children parented and verbal memory performance, showing increasing memory performance with number of children. For mothers, number of children positively correlated with cortical thickness in the parahippocampal gyrus and negatively correlated with regions of the visual cortex. Mothers of one child showed thinner cortical thickness in the dorsolateral prefrontal cortex and visual cortex compared with childless women. Fathers of one child showed thinner cortical thickness in the anterior cingulate cortex and thicker cortical thickness in the temporal pole compared with childless men. Our results are the first to reveal distributed differences in cortical thickness related to parenthood that are evident beyond the postpartum period. Our findings overlap substantially with the areas found to be altered across pregnancy and the postpartum period, suggesting that neural changes associated with early parenthood persist into older age, and are potentially cognitively beneficial.
Brodifacoum does not modulate human cannabinoid receptor-mediated hyperpolarization of AtT20 cells or inhibition of adenylyl cyclase in HEK 293 cells
Authors: Sachdev Shivani , Boyd Rochelle , Grimsey Natasha L , Connor Mark 
Published: March 2019

AbstractBackgroundSynthetic cannabinoids are a commonly used class of recreational drugs that can have significant adverse effects. There have been sporadic reports of co-consumption of illicit drugs with rodenticides such as warfarin and brodifacoum (BFC) over the past 20 years but recently, hundreds of people have been reported to have been poisoned with a mixture of synthetic cannabinoids and BFC. We have sought to establish whether BFC directly affects cannabinoid receptors, or their activation by the synthetic cannabinoid CP55940 or the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC).MethodsThe effects of BFC on the hyperpolarization of wild type AtT20 cells, or AtT20 cells stably expressing human CB1- and CB2-mediated receptors, were studied using a fluorescent assay of membrane potential. The effects of BFC on CB1and CB2mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) activation was measured using a BRET assay of cAMP levels in HEK 293 cells stably expressing human CB1and CB2.ResultsBFC did not activate CB1or CB2receptors, or affect the hyperpolarization of wild type AtT20 cells produced by somatostatin. BFC (10µM) did not affect the hyperpolarization of AtT20-CB1or AtT20-CB2cells produced by CP55940 or Δ9-THC. BFC (1µM) did not affect the inhibition of forskolin-stimulated AC activity by CP55940 in HEK 293 cells expressing CB1or CB2. BFC (1µM) also failed to affect the desensitization of CB1and CB2signalling produced by prolonged (30 min) application of CP55940 or Δ9-THC to AtT20 cells.DiscussionBFC is not a cannabinoid receptor agonist, and appeared not to affect cannabinoid receptor activation. Our data suggests there is no pharmacodynamic rationale for mixing BFC with synthetic cannabinoids, however, it does not speak to whether BFC may affect synthetic cannabinoid metabolism or biodistribution. The reasons underlying the mixing of BFC with synthetic cannabinoids are unknown, and it remains to be established whether the “contamination” was deliberate or accidental. However, the consequences for people who ingested the mixture were often serious, and sometimes fatal, but this seems unlikely to be due to BFC action at cannabinoid receptors.
VRmol: an Integrative Cloud-Based Virtual Reality System to Explore Macromolecular Structure
Authors: Xu Kui , Liu Nan , Xu Jingle , Guo Chunlong , Zhao Lingyun , Wang Hong-Wei , Zhang Qiangfeng Cliff 
Published: March 2019

ABSTRACTPast decades have seen much effort devoted to the tool development for biomacromolecule structural visualization and analysis. In recent years, we have witnessed tremendous advancement in computational technologies, especially in graphics and internet. Here we present an integrative cloud-based, virtual reality (VR) system -- VRmol that exploits these technology advances to visualize and study macromolecule structures in various forms. The immersive environment can improve user experiences in visualization, calculation, and editing of complex structures with more intuitive perception. VRmol is also a system with cloud-based capability to directly access disease-related databases, and couples the structure with genomic variation as well corresponding drugs information in a visual interface, thus serving as an integrative platform to aid structure-based translational research and drug design. VRmol is freely available athttps://VRmol.net.
Phospho-tuning immunity through Denisovan, modern human and mouse TNFAIP3 gene variants
Authors: Zammit Nathan W. , Siggs Owen M. , Gray Paul , Horikawa Keisuke , Daley Stephen R. , Langley David B. , Cultrone Daniele , Malle Elisabeth K. , Walters Stacey N. , Villanueva Jeanette E. , Warren Joanna , Russell Amanda , Cowley Mark J. , Gayevskiy Velimir , Dinger Marcel E. , Loetsch Claudia , King Cecile , Brink Robert , Zahra David , Chaudhri Geeta , Karupiah Gunasegaran , Whittle Belinda , Roots Carla , Bertram Edward , Yamada Michiko , Jeelall Yogesh , Enders Anselm , Clifton Benjamin E. , Mabbitt Peter D. , Jackson Colin J. , Watson Susan R. , Jenne Craig N. , Lanier Lewis L. , Wiltshire Tim , Spitzer Matthew H. , Nolan Garry P. , Schmitz Frank , Aderem Alan , Porebski Benjamin T. , Buckle Ashley M. , Abbott Derek W. , Ziegler John B. , Craig Maria E. , Benitez-Aguirre Paul , Teo Juliana , Wong Melanie , Cox Murray P. , Phung Wilson , Wertz Ingrid E. , Christ Daniel , Goodnow Christopher C. , Grey Shane T. 
Published: March 2019

AbstractResisting or tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here, genomic analyses of anatomically modern humans, extinct Denisovan hominins, and mice revealed a series of missense variants in the immune response inhibitor A20 (encoded byTNFAIP3), substituting non-catalytic residues of the ubiquitin protease domain to diminish IκB-dependent phosphorylation and activation of A20. Two A20 variants with partial phosphorylation deficits appeared beneficial: one originating in Denisovans and introgressed in modern humans throughout Oceania, and another in a mouse strain resistant to Coxsackievirus. By contrast, a variant with 95% loss of phosphorylation caused spontaneous inflammatory disease in humans and mice. Analysis of the partial phosphorylation variant in mice revealed diminished tolerance of bacterial lipopolysaccharide or to poxvirus inoculation as trade-offs for enhanced immunity.One Sentence SummaryModern and ancient variants reveal a genetically tunable element for balancing immunity and microbial tolerance.
Observing an antisense drug complex in intact human cells by in-cell NMR
Authors: Schlagnitweit Judith , Sandoz Sarah Friebe , Jaworski Aleksander , Guzzetti Ileana , Aussenac Fabien , Carbajo Rodrigo J. , Chiarparin Elisabetta , Pell Andrew J. , Petzold Katja 
Published: March 2019

AbstractGaining insight into the uptake of drugs into cells, trafficking and their target engagement enhances understanding of the drug’s function and efficiency. Here we study an antisense oligonucleotide drug (ASO) delivered into HEK293T and HeLa cells, by Nuclear Magnetic Resonance (NMR). Using a combination of transfection, cryoprotection and dynamic nuclear polarization (DNP), we were able to detect the drug directly in intact frozen cells. Activity of the drug was confirmed by qRT-PCR, measuring downregulation of its target mSTAT3. Applying DNP NMR to frozen cells, we overcome limitations of traditional solution-state in-cell NMR (e.g. size, stability and sensitivity) as well as of visualization techniques, where (e.g. fluorescent) tagging of the ASO decreases its activity. The possibility to study an untagged, active drug, interacting in its natural environment, will increase insights into molecular mechanisms of delivery, intracellular trafficking and target engagement in intact cells.
Transgenerational plasticity of inducible defenses: combined effects of grand-parental, parental and current environments
Authors: Tariel Juliette , Plénet Sandrine , Luquet Émilien 
Published: March 2019

ABSTRACTWhile an increasing number of studies highlights that parental environment shapes offspring phenotype (transgenerational plasticity TGP), TGP beyond the parental generation has received less attention. Studies suggest that TGP impacts population dynamics and evolution of phenotype, but these impacts will depend on how long an environmental effect can persist across generations and whether multigenerational effects are cumulative. Here we tested the impact of both grand-parental and parental environments on offspring reaction norm in a prey-predator system. We exposed three generations ofPhysa acutasnails without and with predator-cues according to a full factorial design and measured offspring inducible defenses. We found that both grand-parental and parental exposure to predator cues impacted offspring anti-predator defenses, but their effects were not cumulative and depended on the defenses considered. We also highlighted that grand-parental environment could alter reaction norm of offspring shell thickness, demonstrating an interaction between the grand-parental TGP and the within-generational WGP plasticity. We called for more studies covering the combine effects of multigenerational environments.
The effects of the neonicotinoid imidacloprid on gene expression and DNA methylation in the buff-tailed bumblebee Bombus terrestris
Authors: Bebane P.S.A , Hunt B.J. , Pegoraro M. , Jones A.R.C , Marshall H. , Rosato E. , Mallon E.B. 
Published: March 2019

AbstractNeonicotinoids are effective insecticides used on many important arable and horticultural crops. They are nicotinic acetylcholine receptor agonists which disrupt the function of insect neurons and cause paralysis and death. In addition to direct mortality, there are numerous sublethal effects of low doses of neonicotinoids on bees. We hypothesize that some of these large array of effects could be a consequence of epigenetic changes in bees induced by neonicotinoids. We compared whole methylome (BS-seq) and RNA-seq libraries of the brains of buff tailed bumblebee Bombus terrestris workers exposed to field realistic doses of the neonicotinoid imidacloprid to libraries from control workers. We found numerous genes which show differential expression between neonicotinoid treated bees and control bees, but no differentially methylated cytosines in any context. We found CpG methylation to be focused mainly in exons and associated with highly expressed genes. We discuss the implications of our results for future legislation.
Macro-to-nano scale investigation of wall-plate joints in the acorn barnacle Semibalanus balanoides: correlative imaging, biological form and function, and bioinspiration
Authors: Mitchell R.L , Coleman M. , Davies P. , North L. , Pope E.C. , Pleydell-Pearce C. , Harris W. , Johnston R. 
Published: March 2019

1.AbstractCorrelative imaging combines information from multiple modalities (physical-chemical-mechanical properties) at various length-scales (cm to nm) to understand complex biological materials across dimensions (2D-3D). Here, we have used numerous coupled systems: X-ray microscopy (XRM), scanning electron microscopy (SEM), electron backscatter diffraction (EBSD), optical light microscopy (LM), and focused-ion beam (FIB-SEM) microscopy to ascertain the microstructural and crystallographic properties of the wall-plate joints in the barnacle Semibalanus balanoides. The exoskeleton is composed of six interlocking wall-plates, and the interlocks between neighbouring plates (alae) allow barnacles to expand and grow whilst remaining sealed and structurally strong. Our results indicate that the ala contain functionally-graded orientations and microstructures in their crystallography, which has implications for naturally functioning microstructures, potential natural strengthening, and preferred oriented biomineralisation. Elongated grains at the outer edge of the ala are oriented perpendicularly to the contact surface, and the c-axis rotates with the radius of the ala. Additionally, we identify for the first time three-dimensional nano-scale ala pore networks revealing that the pores are only visible at the tip of the ala, and that pore thickening occurs on the inside (soft-bodied) edge of the plates. The pore networks appear to have the same orientation as the oriented crystallography, and we deduce that the pore networks are probably organic channels and pockets which are involved with the biomineralisation process. Understanding these multi-scale features contributes towards an understanding of the structural architecture in barnacles, but also their consideration for bioinspiration of human-made materials. The work demonstrates that correlative methods spanning different length-scales, dimensions and modes enable the extension of structure-property relationships in materials to form and function of organisms.
Denoising of Aligned Genomic Data
Authors: Fischer-Hwang Irena , Ochoa Idoia , Weissman Tsachy , Hernaez Mikel 
Published: March 2019

ABSTRACTNoise in genomic sequencing data is known to have effects on various stages of genomic data analysis pipelines. Variant identification is an important step of many of these pipelines, and is increasingly being used in clinical settings to aid medical practices. We propose a denoising method, dubbed SAMDUDE, which operates on aligned genomic data in order to improve variant calling performance. Denoising human data with SAMDUDE resulted in improved variant identification in both individual chromosome as well as whole genome sequencing (WGS) data sets. In the WGS data set, denoising led to identification of almost 2,000 additional true variants, and elimination of over 1,500 erroneously identified variants. In contrast, we found that denoising with other state-of-the-art denoisers significantly worsens variant calling performance. SAMDUDE is written in Python and is freely available athttps://github.com/ihwang/SAMDUDE.