bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suboccipital Craniotomy for Resection of a Dorsal Medullary Cerebral Cavernous Malformation: 2-Dimensional Operative Video
Authors: Yagmurlu Kaan , Norat Pedro , Park Min , Kalani M Yashar S 
Published: January 2019

Abstract
This video illustrates the case of a patient with familial cerebral cavernous malformation syndrome with a history of multiple symptomatic hemorrhages attributable to a medullary malformation. The patient had swallowing difficulties and gait instability that was progressively worsening. Informed consent was obtained for surgical exploration. The lesion was noted to abut the floor of the fourth ventricle and was approached using a suboccipital craniotomy. Several safe-entry zones on the floor of the fourth ventricle have been described. For lesions that abut the floor, or those that are exophytic, a direct point of entry into the lesion is selected. When possible, the opening into the floor of the fourth ventricle should be placed off midline. The technique of piecemeal resection of the lesion from the brainstem and preservation of normal, hemosiderin-stained brain is presented. Careful patient selection and respect for normal anatomy are of paramount importance in obtaining excellent outcomes in operations within or adjacent to the brainstem. This medullary lesion was resected completely.
Interfund Lending in Mutual Fund Families: Role in Liquidity Management
Authors: Agarwal Vikas , Zhao Haibei 
Published: January 2019

AbstractThe Investment Company Act of 1940 restricts interfund lending and borrowing within a mutual fund family, but families can apply for regulatory exemptions to participate in such transactions. We find that the monitoring mechanisms and investment restrictions influence the family’s decision to apply for the interfund lending programs. We document several benefits of such programs for equity funds. First, participating funds reduce cash holdings and increase investments in illiquid assets. Second, fund investors exhibit less run-like behavior. Third, it helps mitigate asset fire sales after extreme investor redemptions. Offsetting these benefits, money market funds in participating families experience investor outflows.Received May 26, 2018; editorial decision November 27, 2018 by Editor Itay Goldstein. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Characterizing variants of unknown significance in rhodopsin: a functional genomics approach
Authors: Wan Aliete , Place Emily , Pierce Eric A. , Comander Jason 
Published: January 2019

AbstractCharacterizing the pathogenicity of DNA sequence variants of unknown significance (VUS) is a major bottleneck in human genetics, and is increasingly important in determining which patients with inherited retinal diseases could benefit from gene therapy. A library of 210 rhodopsin (RHO) variants from literature and in-house genetic diagnostic testing was created to efficiently detect pathogenicRHOvariants that fail to express on the cell surface. This study, while focused onRHO, demonstrates a streamlined, generalizable method for detecting pathogenic VUS. A relatively simple next generation sequencing (NGS)-based readout was developed so that a flow cytometry-based assay could be performed simultaneously on all variants in a pooled format, without the need for barcodes or viral transduction. The resulting dataset characterized surface expression of everyRHOlibrary variant with a high degree of reproducibility (Z’=0.94, R2=0.92-0.95), recategorizing 37 variants. For example, three retinitis pigmentosa pedigrees were solved by identifying VUS which showed low expression levels (G18D, G101V, P180T). Results were validated across multiple assays and correlated with clinical disease severity. This study presents a parallelized, higher-throughput cell-based assay for the functional characterization of VUS in rhodopsin, and can be applied more broadly to other inherited retinal disease genes and other disorders.
Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input
Authors: Baaske Magdalena K. , Kormann Eszter , Holt Abbey B. , Gulberti Alessandro , McNamara Colin G. , Pötter-Nerger Monika , Westphal Manfred , Engel Andreas K. , Hamel Wolfgang , Brown Peter , Moll Christian K.E. , Sharott Andrew 
Published: January 2019

AbstractAbnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson’s disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopamine-depleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.
A genetic system for biasing the sex ratio in mice
Authors: Yosef Ido , Edry-Botzer Liat , Globus Rea , Shlomovitz Inbar , Munitz Ariel , Gerlic Motti , Qimron Udi 
Published: January 2019

AbstractThe ability to preselect the sex of livestock is economically beneficial and significantly increases the welfare and proper use of animals. In the poultry industry, for example, almost all males are brutally and unnecessarily killed shortly after hatching. The labor and associated costs of separation of females from males, as well as the massive killing of males, could be reduced by using a system that biases the sex of the progeny. Here, we provide a first proof of concept for such a system by crossing two genetically engineered mouse lines. The maternal line encodes a functional Cas9 protein on an autosomal chromosome, whereas the paternal line encodes guide RNAs on the Y chromosome targeting vital mouse genes. After fertilization, the presence of both the Y-encoded guide RNAs from the paternal sperm and the Cas9 protein from the maternal egg target the vital genes in males. We show that this breeding consequently self-destructs solely the males. Our results pave the way for a biased sex production of livestock, thus saving labor, costs, and eliminating substantial animal suffering.
Challenges and opportunities for strain verification by whole-genome sequencing
Authors: Gallegos Jenna E , Hayrynen Sergei , Adames Neil , Peccoud Jean 
Published: January 2019

AbstractLaboratory strains, cell lines, and other genetic materials change hands frequently in the life sciences. Despite evidence that such materials are subject to mix-ups, contamination, and accumulation of secondary mutations, verification of strains and samples is not an established part of many experimental workflows. With the plummeting cost of next generation technologies, it is conceivable that whole genome sequencing (WGS) could be applied to routine strain and sample verification in the future. To demonstrate the need for strain validation by WGS, we sequenced haploid yeast segregants derived from a popular commercial mutant collection and identified several unexpected mutations. We determined that available bioinformatics tools may be ill-suited for verification and highlight the importance of finishing reference genomes for commonly-used laboratory strains.
Immune gene expression profiling reveals heterogeneity in luminal breast tumors
Authors: Zhu Bin , Ah Tse Shelly Lap , Wang Difei , Koka Hela , Zhang Tongwu , Abubakar Mustapha , Lee Priscilla , Wang Feng , Wu Cherry , Tsang Koon Ho , Chan Wing-cheong , Law Sze Hong , Li Mengjie , Li Wentao , Wu Suyang , Liu Zhiguang , Huang Bixia , Zhang Han , Tang Eric , Kan Zhengyan , Lee Soohyeon , Park Yeon Hee , Nam Seok Jin , Wang Mingyi , Sun Xuezheng , Jones Kristine , Zhu Bin , Hutchinson Amy , Hicks Belynda , Prokunina-Olsson Ludmila , Shi Jianxin , Garcia-Closas Montserrat , Chanock Stephen , Yang Xiaohong R. 
Published: January 2019

AbstractDisease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC-signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification.
Evaluation of a potential redox switch in blood coagulation tenase
Authors: Cook Kristina M. , Butera Diego , Hogg Philip J. 
Published: January 2019

AbstractBlood coagulation factor IXa (FIXa) activates factor X that leads to thrombin and fibrin formation and a stable thrombus. FIXa catalytic efficiency is markedly enhanced when bound to the co-factor, factor VIII (FVIII), and a negatively charged phospholipid surface in the tenase complex. Small redox active peptides and protein oxidoreductases have been shown previously to have some FIXa co-factor activity and thiol modifying agents have been reported to influence FVIII activity. These observations suggested that FIXa might contain an allosteric disulfide that is regulated by FVIII. This idea was tested by measuring the influence of FVIII on the redox state of FIXa disulfide bonds and the effect of plasma oxidoreductases on FIXa activity. The redox state of nine of the 11 disulfide bonds in FIXa was measured using differential cysteine labelling and mass spectrometry and all were oxidized in the protein, and this did not change upon binding of the enzyme to FVIII. All eight disulfide bonds in FVIII were also predominantly oxidized and this did not appreciably change upon FIXa binding. In addition, relevant protein reductants in the circulation inhibited rather than activated FIXa activity. In conclusion, we found no evidence that the co-factor function of FVIII involves a change in the redox state of one or more FIXa disulfide bonds.
The origin of the central dogma through conflicting multilevel selection
Authors: Takeuchi Nobuto , Kaneko Kunihiko 
Published: January 2019

AbstractThe central dogma of molecular biology rests on two kinds of asymmetry between genomes and enzymes: informatic asymmetry, where information flows from genomes to enzymes but not from enzymes to genomes; and catalytic asymmetry, where enzymes provide chemical catalysis but genomes do not. How did these asymmetries originate? Here we show that these asymmetries can spontaneously arise from conflict between selection at the molecular level and selection at the cellular level. We developed a model consisting of a population of protocells, each containing a population of replicating catalytic molecules. The molecules are assumed to face a trade-off between serving as catalysts and serving as templates. This trade-off causes conflicting multilevel selection: serving as catalysts is favoured by selection between protocells, whereas serving as templates is favoured by selection between molecules within protocells. This conflict induces informatic and catalytic symmetry breaking, whereby the molecules differentiate into genomes and enzymes, establishing the central dogma. We show mathematically that the symmetry breaking is caused by a positive feedback between Fisher’s reproductive values and the relative impact of selection at different levels. This feedback induces a division of labour between genomes and enzymes, provided variation at the molecular level is sufficiently large relative to variation at the cellular level, a condition that is expected to hinder the evolution of altruism. Taken together, our results suggest that the central dogma is a logical consequence of conflicting multilevel selection.
Multiplexed temporally focused light shaping through a GRIN lens for precise in-depth optogenetic photostimulation
Authors: Accanto Nicolò , Chen I-Wen , Ronzitti Emiliano , Molinier Clément , Tourain Christophe , Papagiakoumou Eirini , Emiliani Valentina 
Published: January 2019

AbstractIn the past 10 years, the use of light has become irreplaceable for the optogenetic study and control of neurons and neural circuits. Optical techniques are however limited by scattering and can only see through a depth of few hundreds µm in living tissues. GRIN lens based micro-endoscopes represent a powerful solution to reach deeper regions. In this work we demonstrate that cutting edge optical methods for the precise photostimulation of multiple neurons in three dimensions can be performed through a GRIN lens. By spatio-temporally shaping a laser beam in the two-photon regime we project several tens of targets, spatially confined to the size of a single cell, in a volume of 150×150×400 μm3. We then apply such concept to the optogenetic stimulation of multiple neurons simultaneously in vivo in mice. Our work paves the way for an all-optical investigation of neural circuits at previously unattainable depths.
Description ofKlebsiella africanensissp. nov.,Klebsiella variicolasubsp.tropicalensissubsp. nov. andKlebsiella variicolasubsp.variicolasubsp. nov
Authors: Rodrigues Carla , Passet Virginie , Rakotondrasoa Andriniaina , Diallo Thierno Abdoulaye , Criscuolo Alexis , Brisse Sylvain 
Published: January 2019

AbstractThe bacterial pathogenKlebsiella pneumoniaecomprises several phylogenetic groups (Kp1 to Kp7), two of which (Kp5 and Kp7) have no taxonomic status. Here we show that group Kp5 is closely related toKlebsiella variicola(Kp3), with an average nucleotide identity (ANI) of 96.4%, and that group Kp7 has an ANI of 94.7% with Kp1 (K. pneumoniae sensu stricto). Biochemical characteristics and chromosomal beta-lactamase genes also distinguish groups Kp5 and Kp7 from otherKlebsiellataxa. We propose the namesK. africanensisfor Kp7 (type strain, 200023T) andK. variicolasubsp.tropicalensisfor Kp5 (type strain, 1266T).
Morse-clustering of a Topological Data Analysis Network Identifies Phenotypes of Asthma Based on Blood Gene Expression Profiles
Authors: Schofield James P R , Strazzeri Fabio , Bigler Jeannette , Boedigheimer Michael , Adcock Ian M , Chung Kian Fan , Bansal Aruna , Knowles Richard , Dahlen Sven-Erik , Wheelock Craig E. , Sun Kai , Pandis Ioannis , Riley John , Auffray Charles , De Meulder Bertrand , Lefaudeux Diane , Ramanan Devi , Sousa Ana R , Sterk Peter J , Ewing Rob. M , Macarthur Ben D , Djukanovic Ratko , Sanchez-Garcia Ruben , Skipp Paul J 
Published: January 2019

AbstractStratified medicine requires discretisation of disease populations for targeted treatments. We have developed and applied a discrete Morse theory clustering algorithm to a Topological Data Analysis (TDA) network model of 498 gene expression profiles of peripheral blood from asthma and healthy participants. The Morse clustering algorithm defined nine clusters, BC1-9, representing molecular phenotypes with discrete phenotypes including Type-1, 2 & 17 cytokine inflammatory pathways. The TDA network model and clusters were also characterised by activity of glucocorticoid receptor signalling associated with different expression profiles of glucocorticoid receptor (GR), according to microarray probesets targeted to the start or end of the GR mRNA’s 3’ UTR; suggesting differential GR mRNA processing as a possible driver of asthma phenotypes including steroid insensitivity.
Themir-35family links maternal germline sex to embryonic viability inC. elegans
Authors: Benner Lars , Prothro Katherine , McJunkin Katherine 
Published: January 2019

AbstractThe germline sex determination pathway inC. elegansdetermines whether germ cells develop as oocytes or sperm, with no previously known effect on viability. Themir-35family of microRNAs are expressed in theC. elegansgermline and embryo and are essential for both viability and normal hermaphroditic sex determination, preventing aberrant male gene expression in XX hermaphrodite embryos. Here we show that combining feminizing mutations with partial loss of function of themir-35family results in enhanced penetrance embryonic lethality that preferentially kills XO animals. This lethal phenotype is due to altered signaling through the germline sex determination pathway, and maternal germline feminization is sufficient to induce enhanced lethality. These findings reveal a surprising pleiotropy of sperm-fate promoting pathways on organismal viability. Overall, our results demonstrate an unexpectedly strong link between sex determination and embryonic viability, and suggest that in wild type animals,mir-35family members buffer against misregulation of pathways outside the sex determination program, allowing for clean sex reversal rather than deleterious effects of perturbing sex determination genes.
Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action
Authors: Pisansky Marc T. , Lefevre Emilia M. , Retzlaff Cassandra L. , Trieu Brian H. , Leipold David W. , Rothwell Patrick E. 
Published: January 2019

ABSTRACTBackgroundThe nucleus accumbens (NAc) controls multiple facets of impulsivity, but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma aminobutyric acid (GABA) signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of GABA-mediated synaptic inhibition in the NAc.MethodsMale and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task (5-CSRTT) to measure both impulsive action and sustained attention. During the 5-CSRTT, we monitored FSI activity with fiber photometry calcium imaging, and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs.ResultsIn mice performing the 5-CSRTT, NAc FSIs showed sustained activity on trials ending with correct responses, but declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity.ConclusionsThese experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through GABA-mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity, and inform the development of circuit-based therapeutic interventions.
Microtubules are necessary for proper Reticulon localization during mitosis
Authors: Bergman Zane J. , Diaz Ulises , Sims Amanda , Riggs Blake 
Published: January 2019

AbstractDuring mitosis, the structure of the Endoplasmic Reticulum (ER) displays a dramatic reorganization and remodeling event, however the mechanism driving these changes is poorly understood. Recently, the Reticulon family of ER shaping proteins has been identified as possible factors to promote these drastic changes in ER morphology. In addition, the Reticulons and other ER shaping proteins have been directly linked to several hereditary neurodegenerative disorders. Here, we provide key insight into the cytoskeletal factors involved in the Drosophila Reticulon, Reticulon-like 1 (Rtnl1) during mitosis in the early embryo. At prometaphase, Rtnl1 localizes at the spindle poles just prior to the bulk of ER localization suggesting a role in recruitment. Using precise temporal injections of cytoskeletal inhibitors in the early syncytial Drosophila embryo, we show that microtubules, not microfilaments are necessary for proper Rtnl1 localization and function during mitosis. Lastly, we show that astral microtubules are necessary for Rtnl1 localization at the spindle poles early in mitosis. This work highlights the role of the microtubule cytoskeleton in Rtnl1 localization and ER dynamics during mitosis and sheds light on a pathway towards inheritance of this major organelle.
GFP transformation sheds more light on a widespread mycoparasitic interaction
Authors: Németh Márk Z. , Pintye Alexandra , Horváth Áron N. , Vági Pál , Kovács Gábor M. , Gorfer Markus , Kiss Levente 
Published: January 2019

ABSTRACTPowdery mildews (PMs), ubiquitous obligate biotrophic plant pathogens, are often attacked in the field by mycoparasitic fungi belonging to the genus Ampelomyces. Some Ampelomyces strains are commercialized biocontrol agents of crop pathogenic PMs. Using Agrobacterium tumefaciens-mediated transformation (ATMT), we produced stable Ampelomyces transformants that constitutively expressed the green fluorescent protein (GFP), to (i) improve the visualization of the PM-Ampelomyces interaction; and (ii) decipher the environmental fate of Ampelomyces before and after acting as a mycoparasite. Detection of Ampelomyces structures, and especially hyphae, was greatly enhanced when diverse PM, leaf and soil samples containing GFP transformants were examined with fluorescence microscopy compared to brightfield and DIC optics. We showed for the first time that Ampelomyces can persist up to 21 days on PM-free host plant surfaces, where it can attack PM structures as soon as these appear after this period. As a saprobe in decomposing, PM-infected leaves on the ground, and also in autoclaved soil, Ampelomyces developed new hyphae, but did not sporulate. These results indicate that Ampelomyces occupies a niche in the phyllosphere where it acts primarily as a mycoparasite of PMs. Our work has established a framework for a molecular genetic toolbox for Ampelomyces using ATMT.