bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism Underlying Anti-Markovnikov Addition in the Reaction of Pentalenene Synthase
Authors: Matos Jason O. , Kumar Ramasamy P. , Ma Alison C. , Patterson MacKenzie , Krauss Isaac J. , Oprian Daniel D. 
Published: June 2020

AbstractMost terpene synthase reactions follow Markovnikov rules for formation of high energy carbenium ion intermediates. However, there are notable exceptions. For example, pentalenene synthase (PS) undergoes an initial anti-Markovnikov cyclization reaction followed by a 1,2-hydride shift to form an intermediate humulyl cation with positive charge on the secondary carbon C9 of the farnesyl diphosphate substrate. The mechanism by which these enzymes stabilize and guide regioselectivity of secondary carbocations has not heretofore been elucidated. In an effort to better understand these reactions, we grew crystals of apo-PS, soaked them with the non-reactive substrate analog 12,13-difluorofarnesyl diphosphate, and solved the x-ray structure of the resulting complex at 2.2 Å resolution. The most striking feature of the active site structure is that C9 is positioned 3.5 Å above the center of the side chain benzene ring of residue F76, perfectly poised for stabilization of the charge through a cation-π interaction. In addition, the main chain carbonyl of I177 and neighboring intramolecular C6,C7-double bond are positioned to stabilize the carbocation by interaction with the face opposite that of F76. Mutagenesis experiments also support a role for residue 76 in cation-π interactions. Most interesting is the F76W mutant which gives a mixture of products that likely result from stabilizing a positive charge on the adjacent secondary carbon C10 in addition to C9 as in the wild-type enzyme. The crystal structure of the F76W mutant clearly shows carbons C9 and C10 centered above the fused benzene and pyrrole rings of the indole side chain, respectively, such that a carbocation at either position could be stabilized in this complex, and two anti-Markovnikov products, pentalenene and humulene, are formed. Finally, we show that there is a rough correlation (although not absolute) of an aromatic side chain (F or Y) at position 76 in related terpene synthases fromStreptomycesthat catalyze similar anti-Markovnikov addition reactions.
Genomic surveillance of SARS-CoV-2 reveals community transmission of a major lineage during the early pandemic phase in Brazil
Authors: Resende Paola Cristina , Delatorre Edson , Gräf Tiago , Mir Daiana , Motta Fernando do Couto , Appolinario Luciana Reis , da Paixão Anna Carolina Dias , Ogrzewalska Maria , Caetano Braulia , dos Santos Mirleide Cordeiro , de Almeida Ferreira Jessylene , Santos Junior Edivaldo Costa , da Silva Sandro Patroca , Fernandes Sandra Bianchini , Vianna Lucas A , da Costa Souza Larissa , Ferro Jean F G , Nardy Vanessa B , Croda Júlio , Oliveira Wanderson K , Abreu André , Bello Gonzalo , Siqueira Marilda M 
Published: June 2020

AbstractDespite all efforts to control the COVID-19 spread, the SARS-CoV-2 reached South America within three months after its first detection in China, and Brazil became one of the hotspots of COVID-19 in the world. Several SARS-CoV-2 lineages have been identified and some local clusters have been described in this early pandemic phase in Western countries. Here we investigated the genetic diversity of SARS-CoV-2 during the early phase (late February to late April) of the epidemic in Brazil. Phylogenetic analyses revealed multiple introductions of SARS-CoV-2 in Brazil and the community transmission of a major B.1.1 lineage defined by two amino acid substitutions in the Nucleocapsid and ORF6. This SARS-CoV-2 Brazilian lineage was probably established during February 2020 and rapidly spread through the country, reaching different Brazilian regions by the middle of March 2020. Our study also supports occasional exportations of this Brazilian B.1.1 lineage to neighboring South American countries and to more distant countries before the implementation of international air travels restrictions in Brazil.
The projections of ipRGCs and conventional RGCs to retinorecipient brain nuclei
Authors: Beier Corinne , Zhang Ze , Yurgel Maria , Hattar Samer 
Published: June 2020

ABSTRACTRetinal ganglion cells (RGCs), the output neurons of the retina, allow us to perceive our visual environment. RGCs respond to rod/cone input through the retinal circuitry, however, a small population of RGCs are in addition intrinsically photosensitive (ipRGCs) and project to unique targets in the brain to modulate a broad range of subconscious visual behaviors such as pupil constriction and circadian photoentrainment. Despite the discovery of ipRGCs nearly two decades ago, there is still little information about how or if conventional RGCs (non-ipRGCs) target ipRGC-recipient nuclei to influence subconscious visual behavior. Using a dual recombinase color strategy, we showed that conventional RGCs innervate many subconscious ipRGC-recipient nuclei, apart from the suprachiasmatic nucleus. We revealed previously unrecognized stratification patterns of retinal innervation from ipRGCs and conventional RGCs in the ventral portion of the lateral geniculate nucleus. Further, we found that the percent innervation of ipRGCs and conventional RGCs across ipsi- and contralateral nuclei differ. Our data provide a blueprint to understand how conventional RGCs and ipRGCs innervate different brain regions to influence subconscious visual behaviors.
Herbivore-induced activation of viral phosphatase disarms plant antiviral immunities for pathogen transmission
Authors: Zhao Pingzhi , Wang Ning , Yao Xiangmei , Zhu Changxiang , Hogenhout Saskia A. , Liu Shu-sheng , Zhou Xueping , Fang Rongxiang , Ye Jian 
Published: June 2020

AbstractThe survival of pathogens depends on their ability to overcome host immunity, especially arthropod-borne viruses (arboviruses) which must withstand the immune responses of both the host and the arthropod vector. Successful arboviruses often modify host immunity to accelerate pathogen transmission; however, few studies have explored the underlying mechanism. Here we report attracted herbivore infestation on the virus-infected plants promote transmission by the associated vector herbivore. This herbivore-induced defense suppression underpins a subversive mechanism used byBegomovirus, the largest genus of plant viruses, to compromise host defense for pathogen transmission. Begomovirus-infected plants accumulated βC1 proteins in the phloem where they were bound to host defense regulators, transcription factor WRKY20 and two mitogen-activated protein kinases MPK3 and MPK6. Once perceiving whitefly herbivory or endogenous secreted peptide PEP1, the plants started dephosphorylation on serine33and stimulated βC1 protein as a phosphatase. βC1 dephosphorylated MPK3/6 and WRKY20, the latter negatively regulated salicylic acid signaling and vascular callose deposition. This viral hijacking of WRKY20 accumulated more vascular callose by which enforced whitefly prolonged salivation and phloem sap ingestion, therefore impelling more virus transmission among plants. We present a scenario in which viruses dynamically respond to the presence of their vectors, suppressing host immunity and promoting pathogen transmission only when needed.
The genome assembly and annotation ofMagnolia biondiiPamp., a phylogenetically, economically, and medicinally important ornamental tree species
Authors: Dong Shanshan , Liu Min , Liu Yang , Chen Fei , Yang Ting , Chen Lu , Zhang Xingtan , Guo Xing , Fang Dongming , Li Linzhou , Deng Tian , Yao Zhangxiu , Lang Xiaoan , Gong Yiqing , Wu Ernest , Wang Yaling , Shen Yamei , Gong Xun , Liu Huan , Zhang Shouzhou 
Published: June 2020

AbstractMagnolia biondiiPamp. (Magnoliaceae, magnoliids) is a phylogenetically, economically, and medicinally important ornamental tree species widely grown and cultivated in the north-temperate regions of China. Contributing a genome sequence forM. biondiiwill help resolve phylogenetic uncertainty of magnoliids and further understand individual trait evolution inMagnolia. We assembled a chromosome-level reference genome ofM. biondiiusing ~67, ~175, and ~154 Gb of raw DNA sequences generated by Pacific Biosciences Single-molecule Real-time sequencing, 10X genomics Chromium, and Hi-C scaffolding strategies, respectively. The final genome assembly was ⍰2.22 Gb with a contig N50 of 269.11 Kb and a BUSCO complete gene ratio of 91.90%. About 89.17% of the genome length was organized to 19 chromosomes, resulting in a scaffold N50 of 92.86 Mb. The genome contained 48,319 protein-coding genes, accounting for 22.97% of the genome length, in contrast to 66.48% of the genome length for the repetitive elements. We confirmed a Magnoliaceae specific WGD event that might have probably occurred shortly after the split of Magnoliaceae and Annonaceae. Functional enrichment of theMagnoliaspecific and expanded gene families highlighted genes involved in biosynthesis of secondary metabolites, plant-pathogen interaction, and response to stimulus, which may improve ecological fitness and biological adaptability of the lineage. Phylogenomic analyses recovered a sister relationship of magnoliids and Chloranthaceae, which are sister to a clade comprising monocots and eudicots. The genome sequence ofM. biondiicould empower trait improvement, germplasm conservation, and evolutionary studies on rapid radiation of early angiosperms.
HES1 is a Critical Mediator of the SHH-GLI3 Axis in Regulating Digit Number
Authors: Sharma Deepika , Mirando Anthony J. , Leinroth Abigail , Long Jason T. , Karner Courtney M. , Hilton Matthew J. 
Published: June 2020

ABSTRACTSonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. Anterior-posterior SHH/GLI3 signaling gradients regulate cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulatingGrem1to coordinate BMP-induced chondrogenesis. SHH/GLI3 also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a key transcriptional regulator downstream of SHH/GLI signaling capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression ofCdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator,Pax9. These findings fill gaps in knowledge regarding digit number and patterning, while creating a comprehensive framework for our molecular understanding of critical mediators of SHH/GLI3 signaling.
Antibiotic concentrations in the sinonasal secretions and tissue in CRS patients after oral therapy: a randomized trial
Authors: Siu Joey , Klingler Lilian , Wang Yi , Hung Cheung-Tak , Jeong Soo Hee , Smith Susan , Tingle Malcolm , Mackenzie Brett Wagner , Biswas Kristi , Douglas Richard 
Published: June 2020

AbstractBackgroundDespite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa influences their efficacy remains largely undefined.MethodsThirty subjects undergoing functional endoscopic sinus surgery (FESS) for bilateral CRS were randomized to one of three groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days) and 3) control (no antibiotics given). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal secretions, sinonasal tissues and serum at steady state. Nasal endoscopy (Modified Lund-Kennedy) and Gastrointestinal Symptom Rating Scale (GSRS) scores were recorded.ResultsAntibiotic concentrations in the nasal secretions were significantly lower compared to those in the serum and tissue (mean mucus/serum ratio at steady state = 0.16 and 0.37 for doxycycline and roxithromycin respectively;p<0.01). A short course of antibiotic intake did not correlate with any difference in clinical outcomes except where slightly higher GSRS scores were reported in the roxithromycin group (p=0.04).ConclusionsAlthough the efficacy of doxycycline and roxithromycin in sinonasal mucusin vivocannot be predicted solely from reported minimum inhibitory concentrations, given the added complication of bacterial biofilm antimicrobial tolerance, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS.
A new system in qualitative RT-PCR detecting SARS-CoV-2 in biological samples: an Italian experience
Authors: Favaro Marco , Mattina Walter , Pistoia Enrico Salvatore , Gaziano Roberta , Di Francesco Paolo , Middleton Simon , D’Angelo Silvia , Altarozzi Tullio , Fontana Carla 
Published: June 2020

ABSTRACTIn the last moths the world was faced with the pandemic of a new severe acute respiratory syndrome coronavirus (SARS-CoV) and the majority of the Nations have yet to come out of it. Numerous assays have emerged to meet SARS-CoV-2 diagnostic needs. A clear knowledge of these assays’ parameters is essential to choose the proper test by clinical microbiologists. Unfortunately, the latter cannot be the unique criterion that guides test selection as - given the great demand - shortcomings of commercial kits is also a great issue. Aimed by the intention of overcoming both difficulties we have developed a new qualitative RT-PCR probe based for COVID-19 detection. The system detects three genes of SARS-CoV-2: RNA-dependent RNA polymerase (RdRp), envelope (E) and nucleocapsid (N) and β-actin gene used as endogenous internal control. The results of our assay show a total agreement with those obtained using a commercially available kit, with the exception of two specimens which did not pass the endogenous internal control. Moreover, our kit was designed to be open either for nucleic acid extraction step or on the RT-PCR assay to be carried out on several instruments. Thus, it is free from the industrial production logics of closed systems and conversely it is hypothetically available for distribution on large numbers in any microbiological laboratories. Presently, the kit is currently distributed worldwide
GWAS of stool frequency reveals genes, pathways, and cell types relevant to human gastrointestinal motility and irritable bowel syndrome
Authors: Bonfiglio Ferdinando , Liu Xingrong , Smillie Christopher , Pandit Anita , Kurilshikov Alexander , Bacigalupe Rodrigo , Zheng Tenghao , Nim Hieu , Garcia-Etxebarria Koldo , Bujanda Luis , Andreasson Anna , Agreus Lars , Walter Susanna , Abecasis Goncalo , Eijsbouts Chris , Jostins Luke , Parkes Miles , Hughes David A , Timpson Nicholas , Raes Jeroen , Franke Andre , Kennedy Nicholas A , Regev Aviv , Zhernakova Alexandra , Simren Magnus , Camilleri Michael , D’Amato Mauro 
Published: June 2020

ABSTRACTObjectiveGut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders (FGID) like irritable bowel syndrome (IBS). Its molecular underpinnings, and their anomalies in FGID disorders are poorly characterized, hence we sought to gain mechanistic insight through a large-scale genetic investigation.DesignWe used stool frequency (STL-FRQ) as a (surrogate) quantitative trait to study the genetics of gut motility, exploiting questionnaire and genotype data from UK Biobank and four smaller population-based cohorts (LifeLines-Deep, Genes for Good, Flemish Gut Flora Project and PopCol), in a GWAS meta-analysis spanning 8,817,117 high-quality SNP markers and 167,875 individuals of European descent.ResultsWe identify 13 genome-wide significant loci (P≤5.0×10−8) harboring prioritized genes that are: i) involved in sensory perception and neurotransmitter/neuropeptide signaling; ii) enriched for their expression in enteric motor neurons associated with the control of peristalsis (P=7.0×10−8) iii) previously linked to other traits and conditions, including GI motility and dysmotility syndromes, and the response to their pharmacological treatment. The genetic architecture of STL-FRQ most strongly correlates with that of IBS (rg=0.42; P=1.1×10−3). In UK Biobank, the risk of IBS with diarrhea was 4x higher in individuals from the top 1% of the distribution of polygenic scores (PGS) computed based on STL-FRQ GWAS summary statistics (ORs=4.14; P=1.2×10−97).ConclusionWe identify loci harboring genes with a plausible role in GI motility, possibly acting via neurotransmission and similar pathways in specialized enteric neurons. The demonstrated relevance of these findings to IBS warrants further study for the identification of actionable pathomechanisms in the dysmotility syndromes.
Two distinct immunopathological profiles in autopsy lungs of COVID-19
Authors: Nienhold Ronny , Ciani Yari , Koelzer Viktor H. , Tzankov Alexandar , Haslbauer Jasmin D. , Menter Thomas , Schwab Nathalie , Henkel Maurice , Frank Angela , Zsikla Veronika , Willi Niels , Kempf Werner , Hoyler Thomas , Barbareschi Mattia , Moch Holger , Tolnay Markus , Cathomas Gieri , Demichelis Francesca , Junt Tobias , Mertz Kirsten D. 
Published: June 2020

AbstractCoronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Therefore we conducted transcriptomic, histologic and cellular profiling ofpost mortemCOVID-19 (n=34 tissues from 16 patients) and normal lung tissues (n=9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 were identified. One pattern showed high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern showed severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhighpatients died significantly earlier after hospitalization than ISGlowpatients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.
Development of a SARS-CoV-2 total antibody assay and the dynamics of antibody response over time in hospitalized and non-hospitalized patients with COVID-19
Authors: Vogelzang Erik H. , Loeff Floris C. , Derksen Ninotska IL , Kruithof Simone , Heer Pleuni Ooijevaar-de , van Mierlo Gerard , Linty Federica , Mok Juk Yee , van Esch Wim , de Bruin Sanne , Vlaar Alexander P.J. ,   AmsterdamUMC COVID-19 biobank study group, Seppen Bart , Leeuw Maureen , van Oudheusden Anne J.G. , Buiting Anton G.M. , Jim Kin Ki , Vrielink Hans , Swaneveld Francis , Vidarsson Gestur , van der Schoot C. Ellen , Wever Peter , Li Wentao , van Kuppeveld Frank , Murk Jean-Luc , Bosch Berend Jan , Wolbink Gerrit-Jan , Rispens Theo 
Published: June 2020

AbstractSARS-CoV-2 infections often cause only mild disease that may evoke relatively low antibody titers compared to patients admitted to hospitals. Generally, total antibody bridging assays combine good sensitivity with high selectivity. Therefore, we developed sensitive total antibody bridging assays for detection of SARS-CoV-2 antibodies to the receptor-binding domain (RBD) and nucleocapsid protein (NP), in addition to conventional isotype-specific assays. Antibody kinetics was assessed in PCR-confirmed hospitalized COVID-19 patients (n=41) and three populations of patients with COVID-19 symptoms not requiring hospital admission: PCR-confirmed convalescent plasmapheresis donors (n=182), PCR-confirmed hospital care workers (n=47), and a group of longitudinally sampled symptomatic individuals highly suspect of COVID-19 (n=14). In non-hospitalized patients, the antibody response to RBD is weaker but follows similar kinetics as has been observed in hospitalized patients. Across populations, the RBD bridging assay identified most patients correctly as seropositive. In 11/14 of the COVID-19-suspect cases, seroconversion in the RBD bridging assay could be demonstrated before day 12; NP antibodies emerged less consistently. Furthermore, we demonstrated the feasibility of finger prick sampling for antibody detection against SARS-CoV-2 using these assays. In conclusion, the developed bridging assays reliably detect SARS-CoV-2 antibodies in hospitalized and non-hospitalized patients, and are therefore well-suited to conduct seroprevalence studies.
Assessing the effect of global travel and contact reductions to mitigate the COVID-19 pandemic and resurgence
Authors: Lai Shengjie , Ruktanonchai Nick W , Carioli Alessandra , Ruktanonchai Corrine W , Floyd Jessica R , Prosper Olivia , Zhang Chi , Du Xiangjun , Yang Weizhong , Tatem Andrew J 
Published: June 2020

AbstractTravel and physical distancing interventions have been implemented across the World to mitigate the COVID-19 pandemic, but studies are needed to quantify the effectiveness of these measures across regions and time. Timely population mobility data were obtained to measure travel and contact reductions in 135 countries or territories. During the 10 weeks of March 22 – May 30, 2020, domestic travel in study regions has dramatically reduced to a median of 59% (interquartile range [IQR] 43% - 73%) of normal levels seen before the outbreak, with international travel down to 26% (IQR 12% - 35%). If these travel and physical distancing interventions had not been deployed across the World, the cumulative number of cases might have shown a 97-fold (IQR 79 – 116) increase, as of May 31, 2020. However, effectiveness differed by the duration and intensity of interventions and relaxation scenarios, with variations in case severity seen across populations, regions, and seasons.One Sentence SummaryTravel and physical distancing interventions across the World are key to mitigate the COVID-19 pandemic and resurgence.