bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shed skin as a source of DNA for genotyping-by-sequencing (GBS) in reptiles
Authors: Brekke Thomas D , Shier Liam , Hegarty Matthew J , Mulley John F 
Published: June 2019

AbstractOver a fifth of reptile species are classified as ‘Threatened’ and conservation efforts, especially those aimed at recovery of isolated or fragmented populations, will require genetic and genomic data and resources. Shed skins of snakes and other reptiles contain DNA, are a safe and ethical way of non-invasively sampling large numbers of individuals, and provide a simple mechanism by which to involve the public in scientific research. Here we test whether the DNA in dried shed skin is suitable for reduced representation sequencing approaches, specifically genotyping-by-sequencing (GBS). Shed skin-derived libraries resulted in fewer sequenced reads than those from snap-frozen muscle samples, and contained slightly fewer variants (70,685 SNPs versus 97,724), but this issue can easily be rectified with deeper sequencing of shed skin-derived libraries. Skin-derived libraries also have a very slight (but significantly different) profile of transitions and transversions, most likely as a result of DNA damage, but the impact of this is minimal given the large number of single nucleotide polymorphisms (SNPs) involved. SNP density tends to scale with chromosome length, and microchromosomes have a significantly higher SNP density than macrochromosomes, most likely because of their higher GC content. Overall, shed skin provides DNA of sufficient quality and quantity for the identification of large number of SNPs, but requires greater sequencing depth, and consideration of the GC richness of microchromosomes when selecting restriction enzymes.
Termination of pre-mRNA splicing requires that the ATPase and RNA unwindase Prp43 acts on the catalytic snRNA U6
Authors: Toroney Rebecca , Nielsen Klaus H. , Staley Jonathan P. 
Published: June 2019

AbstractThe termination of pre-mRNA splicing functions to discard suboptimal substrates, thereby enhancing fidelity, and to release excised introns in a manner coupled to spliceosome disassembly, thereby allowing recycling. The mechanism of termination, including the RNA target of the DEAH-box ATPase Prp43, remains ambiguous. We discovered a critical role for nucleotides at the 3’-end of the catalytic U6 small nuclear RNA in splicing termination. Though conserved sequence at the 3’-end is not required, 2’ hydroxyls are, paralleling requirements for Prp43 biochemical activities. While the 3’-end of U6 is not required for recruiting Prp43 to the spliceosome, the 3’ end crosslinks directly to Prp43 in an RNA-dependent manner. Our data indicate a mechanism of splicing termination in which Prp43 translocates along U6 from the 3’ end to disassemble the spliceosome and thereby release suboptimal substrates or excised introns. This mechanism reveals that the spliceosome becomes primed for termination at the same stage it becomes activated for catalysis, implying a requirement for stringent control of spliceosome activity within the cell.
The Evolution of Fluoroquinolone-Resistance inMycobacterium tuberculosisis Modulated by the Genetic Background
Authors: Castro Rhastin A. D. , Ross Amanda , Kamwela Lujeko , Reinhard Miriam , Loiseau Chloé , Feldmann Julia , Borrell Sonia , Trauner Andrej , Gagneux Sebastien 
Published: June 2019

AbstractFluoroquinolones (FQ) form the backbone in experimental treatment regimens against drug-susceptible tuberculosis. However, little is known on whether the genetic variation present in natural populations ofMycobacterium tuberculosis(Mtb) affects the evolution of FQ-resistance (FQ-R). To investigate this question, we used a set ofMtbstrains that included nine genetically distinct drug-susceptible clinical isolates, and measured their frequency of resistance to the FQ ofloxacin (OFX)in vitro. We found that theMtbgenetic background led to differences in the frequency of OFX-resistance (OFX-R) that spanned two orders of magnitude and substantially modulated the observed mutational profiles for OFX-R. Furtherin vitroassays showed that the genetic background also influenced the minimum inhibitory concentration and the fitness effect conferred by a given OFX-R mutation. To test the clinical relevance of ourin vitrowork, we surveyed the mutational profile for FQ-R in publicly available genomic sequences from clinicalMtbisolates, and found substantialMtblineage-dependent variability. Comparison of the clinical and thein vitromutational profiles for FQ-R showed that 45% and 19% of the variability in the clinical frequency of FQ-RgyrAmutations in Lineage 2 and Lineage 4 strains, respectively, can be attributed to howMtbevolves FQ-Rin vitro. As theMtbgenetic background strongly influenced the evolution of FQ-Rin vitro, we conclude that the genetic background ofMtbalso impacts the evolution of FQ-R in the clinic.SignificanceNewer generations of fluoroquinolones form the backbone in many experimental treatment regimens againstM. tuberculosis(Mtb). While the genetic variation in natural populations ofMtbcan influence resistance evolution to multiple different antibiotics, it is unclear whether it modulates fluoroquinolone-resistance evolution as well. Using a combination ofin vitroassays coupled with genomic analysis of clinical isolates, we provide the first evidence illustrating theMtbgenetic background’s substantial role in fluoroquinolone-resistance evolution, and highlight the importance of bacterial genetics when studying the prevalence of fluoroquinolone-resistance inMtb. Our work may provide insights into how to maximize the timespan in which fluoroquinolones remain effective in clinical settings, whether as part of current standardized regimens, or in new regimens againstMtb.
“A distinct neutrophil population invades the central nervous system during pancreatic cancer”
Authors: Burfeind Kevin G. , Zhu Xinxia , Norgard Mason A. , Levasseur Peter R. , Olson Brennan , Michaelis Katherine A. , Torres Eileen Ruth S. , Patel Esha M. , Jeng Sophia , McWeeney Shannon , Raber Jacob , Marks Daniel L. 
Published: June 2019

AbstractWeight loss, fatigue, and cognitive dysfunction are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. CCR2 knockout mice had significantly decreased brain-infiltrating neutrophils as well as attenuated anorexia and muscle catabolism during PDAC, without any changes in neutrophils in other organs. Lastly, intracerebroventricular blockade of the purinergic receptor P2RX7 during PDAC abolished neutrophil recruitment to the brain and attenuated anorexia. Our data demonstrate a novel function for the CCR2/CCL2 axis in recruiting neutrophils to the brain, which drives anorexia and muscle catabolism.
Asymmetrical cleavages ofSleeping Beautytransposons generate multiple excised transposon fragments during transposition
Authors: Gu Qilin , Yang Xiaojie , Li Qing , Long Yong , Song Guili , Pei Desheng , Hackett Perry B. , Chen Jun , Peng Jinrong , Cui Zongbin 
Published: June 2019

ABSTRACTAlthough theSleeping Beauty(SB) transposon is the most validated DNA transposon used as a gene delivery vehicle in vertebrates, many details of the excision and integration steps in the transposition process are unclear. We have probed in detail the products of the excision step and apparent selective integration of a subset of those products during transposition. The standard model of SB transposase-mediated transposition includes symmetrical cleavages at both ends of the transposon for excision and re-integration in another DNA sequence. In our analysis of excised transposon fragments (ETFs), we found evidence for the requirement of certain flanking sequences for efficient cleavage and a significant rate of asymmetrical cleavage during the excision process that generates multiple ETFs. Our results suggest that the cleavage step by SB transposase is not as precise as indicated in most models. Repair of the donor ends can produce eight footprint sequences (TACTGTA, TACAGTA, TACATA, TACGTA, TATGTA, TACTA, TAGTA and TATA). Our data also suggest that mismatch repair (MMR) is not an essential requirement for footprint formation. Among the twenty liberated ETFs, only eight appear to effectively re-integrate into TA sites distributed across the genome, supporting earlier findings of unequal rates of excision and reintegration during SB transposition. These findings may be important in considerations of efficiency of SB transposon remobilization, selection of TA integration sites and detection of SB excision and integration loci, all of which may be important in human gene therapy.
Variations and expression features of CYP2D6 contribute to schizophrenia risk
Authors: Ma Liang , Chetty Sundari 
Published: June 2019

ABSTRACTObjectiveGenome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown.MethodsHere, we analyze 1,479 RNA-seq data from 13 postmortem brain regions in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Then, we co-localize eGene and eJunction with SCZ GWAS using SMR and mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for identifying the causative variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) enrichment analysis to determine implicated pathways.ResultsWe identified 171 genes and eight splicing junctions located within four genes (SNX19, ARL6IP4, APOPT1 and CYP2D6) that potentially contribute to SCZ susceptibility. Among the genes, CYP2D6 is significantly associated with SCZ SNPs in both eGene and eJunction across the 13 brain regions. In-depth examination of the CYP2D6 region revealed that a non-synonymous single nucleotide variant (SNV) rs16947 is strongly associated with a higher abundance of CYP2D6 exon 3 skipping junctions. While we found rs133377 and two other SNPs in high linkage disequilibrium (LD) with rs16947 (r2 = 0.9539), histone acetylation analysis showed they are located within active transcription start sites. Furthermore, our data-driven enrichment analysis showed CYP2D6 is significantly involved in drug metabolism of tamoxifen, codeine and citalopram.ConclusionsOur study facilitates an understanding of the genetic architecture of SCZ and provides new drug targets.
Molecular pathway analysis indicates a distinct metabolic and immune phenotype in women with right-sided colon cancer
Authors: Sun Yazhi , Mironova Varvara , Chen Ying , Lundh Elliott P.F. , Zhang Qian , Cai Yuping , Vasiliou Vasilis , Zhang Yawei , Garcia-Milian Rolando , Khan Sajid A. , Johnson Caroline H. 
Published: June 2019

AbstractColon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men do. However, women have a higher propensity for RCC than men. Identification of gene expression differences between RCC and LCC is considered a potential means of prognostication. Furthermore, studying colon cancer sidedness could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancer using four publicly available annotated datasets housed in the National Center for Biotechnology Information’s Gene Expression Omnibus (GEO). We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared to women with LCC. Specifically, we showed that the downregulation of 5’ AMP-activated protein kinase alpha subunit (AMPKα) and downregulated anti-tumor immune response in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.
Ribosomal protein RACK1 facilitates efficient translation of poliovirus and other viral IRESs
Authors: LaFontaine Ethan , Miller Clare M. , Permaul Natasha , Johnson Alex G. , Martin Elliot T. , Fuchs Gabriele 
Published: June 2019

AbstractViruses have evolved various strategies to ensure efficient translation using host cell ribosomes and translation factors. In addition to cleaving translation initiation factors required for host cell translation, poliovirus (PV) uses an internal ribosome entry site (IRES) to bypass the need for these translation initiation factors. Recent studies also suggest that viruses have evolved to exploit specific ribosomal proteins to enhance translation of their viral proteins. The ribosomal protein receptor for activated C kinase 1 (RACK1), a protein of the 40S ribosomal subunit, was previously shown to mediate translation of the 5′ cricket paralysis virus and hepatitis C virus IRESs. Here we found that while translation of a PV dual-luciferase reporter shows only a moderate dependence on RACK1, PV translation in the context of a viral infection is drastically reduced. We observed significantly reduced poliovirus plaque size and a delayed host cell translational shut-off suggesting that loss of RACK1 increases the length of the virus life cycle. Our findings further illustrate the involvement of the cellular translational machinery in PV infection and how viruses usurp the function of specific ribosomal proteins.
Space is the Place: Effects of Continuous Spatial Structure on Analysis of Population Genetic Data
Authors: Battey C.J. , Ralph Peter L. , Kern Andrew D. 
Published: June 2019

ABSTRACTReal geography is continuous, but standard models in population genetics are based on discrete, well-mixed populations. As a result many methods of analyzing genetic data assume that samples are a random draw from a well-mixed population, but are applied to clustered samples from populations that are structured clinally over space. Here we use simulations of populations living in continuous geography to study the impacts of dispersal and sampling strategy on population genetic summary statistics, demographic inference, and genome-wide association studies. We find that most common summary statistics have distributions that differ substantially from that seen in well-mixed populations, especially when Wright’s neighborhood size is less than 100 and sampling is spatially clustered. Stepping-stone models reproduce some of these effects, but discretizing the landscape introduces artifacts which in some cases are exacerbated at higher resolutions. The combination of low dispersal and clustered sampling causes demographic inference from the site frequency spectrum to infer more turbulent demographic histories, but averaged results across multiple simulations were surprisingly robust to isolation by distance. We also show that the combination of spatially autocorrelated environments and limited dispersal causes genome-wide association studies to identify spurious signals of genetic association with purely environmentally determined phenotypes, and that this bias is only partially corrected by regressing out principal components of ancestry. Last, we discuss the relevance of our simulation results for inference from genetic variation in real organisms.
Amplifying the Neural Power Spectrum
Authors: Doyle J. Andrew , Toussaint Paule-Joanne , Evans Alan C. 
Published: June 2019

AbstractWe introduce a novel method that employs a parametric model of human electroen-cephalographic (EEG) brain signal power spectra to evaluate cognitive science experiments and test scientific hypotheses. We develop the Neural Power Amplifier (NPA), a data-driven approach to EEG pre-processing that can replace current filtering strategies with a principled method based on combining filters with log-arithmic and Gaussian magnitude responses. Presenting the first time domain evidence to validate an increasingly popular model for neural power spectra [1], we show that filtering out the 1/f background signal and selecting peaks improves a time-domain decoding experiment for visual stimulus of human faces versus random noise.
Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines
Authors: Ali Farhan , Gerhard Danielle M. , Sweasy Katherine , Pothula Santosh , Pittenger Christopher , Duman Ronald S. , Kwan Alex C. 
Published: June 2019

AbstractA subanesthetic dose of ketamine causes acute psychotomimetic symptoms and then more sustained antidepressant effects. A key targeted brain region is the prefrontal cortex, and the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine may act preferentially on GABAergic neurons. However, cortical GABAergic neurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that administration of ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.
Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice
Authors: Assous Maxime , Martinez Edward , Eisenberg Carol , Kosc Aleksandra , Varghese Kristie , Espinoza Diego , Bhimani Shaznaan , Shah Fulva , Tepper James M. , Shiflett Michael W. , Tran Tracy S. 
Published: June 2019

AbstractThe striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2-/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and semaphorin signaling.Significance StatementThe corticostriatal pathway controls sensorimotor, learning and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that neuropilin 2 (Nrp2), a receptor for the axon-guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs and learning in mice. Our findings, coupled with Nrp2’s association with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 as a key regulator of corticostriatal development, maintenance and function, and may lead to better understanding of neurodevelopmental disease mechanisms.
Baseline Semantic Fluency Is Associated with Six-Year Progression to Mild Cognitive Impairment in Middle-Aged Men
Authors: Gustavson Daniel E. , Elman Jeremy A. , Panizzon Matthew S. , Franz Carol E. , Zuber Jordan , Sanderson-Cimino Mark , Reynolds Chandra A. , Jacobson Kristen C. , Xian Hong , Jak Amy J. , Toomey Rosemary , Lyons Michael J. , Kremen William S. 
Published: June 2019

AbstractObjectiveTest the hypothesis that individual differences in episodic memory and verbal fluency in cognitively normal middle-aged adults will predict progression to amnestic MCI after 6 years.MethodThe analysis sample included 842 male twins who were cognitively normal at baseline (M=56 years), completed measures of episodic memory and verbal fluency at baseline and again 6 years later (M=62 years).ResultsPoor episodic memory predicted progression to both amnestic MCI (OR=4.42, 95% CI [2.44, 10.60]) and non-amnestic MCI (OR=1.92, 95% CI [1.32, 3.44]). Poor semantic verbal fluency also independently predicted progression to amnestic MCI (OR=1.86, 95% CI [1.12, 3.52]). In the full sample, a semantic-specific fluency latent variable at wave 1 (which controls for letter fluency) predicted change in episodic memory at wave 2 (β=.13), but not vice-versa (β=.04). Associations between episodic memory and verbal fluency factors were primarily explained by genetic, rather than environmental, correlations.ConclusionsAmong individuals who were cognitively normal at wave 1, episodic memory moderately-to-strongly predicted progression to MCI at average age 62, emphasizing the fact that there is still meaningful variability even among cognitively normal individuals. Episodic memory, which is typically a primary focus for AD risk, declined earlier and more quickly than fluency. However, semantic fluency at average age 56 predicted 6-year change in memory as well as progression to amnestic MCI even after accounting for baseline memory performance. These findings emphasize the utility of memory and fluency measures in early identification of AD risk.