bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of high-dose exposure in transmission hot zones as a driver of SARS-CoV2 dynamics
Authors: Wodarz Dominik , Komarova Natalia L. , Schang Luis M. 
Published: October 2020

AbstractEpidemiological data on the spread of SARS-CoV-2 in the absence and presence of various non-pharmaceutical interventions indicate that the virus is not transmitted uniformly in the population. Transmission tends to be more effective in select settings that involve exposure to relatively high viral dose, such as in crowded indoor settings, assisted living facilities, prisons, or food processing plants. To explore the effect on infection dynamics, we describe a new mathematical model where transmission can occur (i) in the community at large, characterized by low dose exposure and mostly mild disease, and (ii) in so called transmission hot zones, characterized by high dose exposure that can be associated with more severe disease. Interestingly, we find that successful infection spread can hinge upon high-dose hot zone transmission, yet the majority of infections are predicted to occur in the community at large with mild disease. This gives rise to the prediction that targeted interventions that specifically reduce virus transmission in the hot zones (but not in the community at large) have the potential to suppress overall infection spread, including in the community at large. The model can further reconcile seemingly contradicting epidemiological observations. While in some locations like California, strict stay-home orders failed to significantly reduce infection prevalence, in other locations, such as New York and several European countries, stay-home orders lead to a pronounced fall in infection levels, which remained suppressed for some months after re-opening of society. Differences in hot zone transmission levels during and after social distancing interventions can account for these diverging infection patterns. These modeling results warrant further epidemiological investigations into the role of high dose hot zone transmission for the maintenance of SARS-CoV-2 spread.
Report on COVID-19 Verification Case Study in Nine Countries Using the SIQR model
Authors: Suda Reiji 
Published: October 2020

AbstractThis report uses the SIQR model proposed by Takashi Odagaki to examine the epidemic trend of COVID-19 in nine major countries during February-May 2020, and to clarify the peculiar trend of infection in Japan. The SIQR model, which is an improvement on the conventional SIR model, is unique in that it allows us to theoretically clarify the epidemic phenomenon by separating the number of daily confirmed new cases by testing and the number of infecteds at large who remain untested, and also allows us to theoretically consider measures to control the epidemic. The infection control measures of each country were analyzed by dividing them into three groups according to the size of the decay (or growth) rate of infected at large (λ). The active group includes China and South Korea, the passive group includes the United States and Sweden, and the average group includes Germany, Italy, France, Spain, and Japan. China and South Korea are the countries with the best testing and quarantine systems, and South Korea in particular having managed to contain the infection without lockdown through early quarantine by thorough testing. On the other hand, the United States and Sweden do not have a well-developed inspection and quarantine system and have shown little restraint in social distancing. In the case of Japan, the following special factors may have contributed to the extreme lack of PCR testing : (1) The “4-day fever rule” established by the Ministry of Health, Labour and Welfare was strictly enforced. (2) Even after the decision to postpone the Olympics, the government continued to monopolize PCR testing for the sake of unified analysis of infection data, and the policy of expanding PCR testing by private companies was not implemented.
Cost-effectiveness of Dengue Vaccination in Puerto Rico
Authors: España Guido , Leidner Andrew J. , Waterman Stephen , Perkins T. Alex 
Published: October 2020

ABSTRACTAn effective and widely used vaccine could reduce the burden of dengue virus (DENV) around the world. DENV is endemic in Puerto Rico, where the dengue vaccine CYD-TDV is currently under consideration as a control measure. CYD-TDV has demonstrated efficacy in clinical trials in vaccinees who had prior dengue infection. However, in vaccinees who had no prior dengue infection, the vaccine had a modestly elevated risk of hospitalization and severe disease. The WHO therefore recommended a strategy of pre-vaccination screening and vaccination of seropositive persons. To estimate the cost-effectiveness and benefits of this intervention (i.e., screening and vaccination of seropositive persons) in Puerto Rico, we simulated 10 years of the intervention in 9-year-olds using an agent-based model. Across the entire population, we found that 5.5% (4.6%-6.3%) of dengue hospitalizations could be averted. However, we also found that 1.6 (1.3 - 2.1) additional hospitalizations could occur for every 1,000 DENV-naïve children who were vaccinated following a false-positive test results for prior exposure. The ratio of the averted hospitalizations among all vaccinees to additional hospitalizations among DENV-naïve vaccinees was estimated to be 19 (13-24). At a base case cost of vaccination of 382 USD, we found an incremental cost-effectiveness ratio of 122,000 USD per QALY gained. Our estimates can provide information for considerations to introduce the CYD-TDV vaccine in Puerto Rico.
Pharmacological inhibition of the ALK axis elicits therapeutic potential in Consensus Molecular Subtype 1 colon cancer patients
Authors: Mazzeschi Martina , Sgarzi Michela , Romaniello Donatella , Gelfo Valerio , Cavallo Carola , Santi Spartaco , Fiorentino Michelangelo , D’Uva Gabriele , Győrffy Balázs , Palmer Ruth , Lauriola Mattia 
Published: October 2020

AbstractIn the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). In this work, we performed a meta-analysis of 1700 CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested several CMSsin vitromodels with crizotinib (CZB) or alectinib (ALC), potent ALK inhibitors, already approved for clinical use. ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore,in vivoimaging identified a role for ALK in the dynamic formation of 3D spheroids, which was impaired by the pharmacological inhibition of ALK. Consistently, CZB was responsible for the dampened activation of ALK along with the downstream AKT cascade. Mechanistically, we found a specific pro-apoptotic effect of ALK inhibition in CMS1 cell lines, both in 2D and 3D. Confocal analysis suggests that inhibition in CMS1 cells enhances cell-cell adhesion when growing in 3D. In agreement with our findings, an ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, the efficacy of ALK inhibition treatment was demonstrated in patient-derived organoids. Collectively, our findings suggest that ALK inhibition may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.
COUP-TFI regulates diameter of the axon initial segment in the mammalian neocortex
Authors: Wu Xuanyuan , Li Haixiang , Huang Jiechang , Xiao Cheng , He Shuijin 
Published: October 2020

AbstractThe axon initial segment is a specialized structure that controls neuronal excitability by generating action potentials. Currently, AIS plasticity with regard to changes in length and location in response to neural activity has been extensively investigated, but how AIS diameter is regulated remains elusive. Here we report that COUP-TFI is an essential regulator of AIS diameter in both developing and adult mouse neocortex. Embryonic ablation of COUP-TFI prevented expansion of AIS diameter that occurs during postnatal development in layer II/III pyramidal cells of the mouse motor cortex, thereby leading to an impairment of action potential generation. Inactivation of COUP-TFI in adult neurons also led to reduced AIS diameter and impaired action potential generation. In contrast to different developmental stages, single-cell ablation and global ablation produced opposite effects on spontaneous network in COUP-TFI-deficient neurons. Further, mice exhibited less anxiety-like behaviors after postnatal inactivation of COUP-TFI induced by tamoxifen. Our results demonstrate that COUP-TFI is indispensable for both expansion and maintenance of AIS diameter and that a change in AIS diameter fine-tunes synaptic inputs through a metaplasticity mechanism in the adult neocortex.
Schengen-pathway controls spatially separated and chemically distinct lignin deposition in the endodermis
Authors: Reyt Guilhem , Ramakrishna Priya , Salas-González Isai , Fujita Satoshi , Love Ashley , Tiemessen David , Lapierre Catherine , Morreel Kris , Polanco Monica Calvo , Flis Paulina , Geldner Niko , Boursiac Yann , Boerjan Wout , George Michael W. , Castrillo Gabriel , Salt David E. 
Published: October 2020

ABSTRACTLignin is a complex polymer precisely deposited in the cell wall of specialised plant cells, where it provides essential cellular functions. Plants coordinate timing, location, abundance and composition of lignin deposition in response to endogenous and exogenous cues. In roots, a fine band of lignin, the Casparian strip encircles endodermal cells. This forms an extracellular barrier to solutes and water and plays a critical role in maintaining nutrient homeostasis. A signalling pathway senses the integrity of this diffusion barrier and can induce over-lignification to compensate for barrier defects. Here, we report that activation of this endodermal sensing mechanism triggers a transcriptional reprogramming strongly inducing the phenylpropanoid pathway and immune signaling. This leads to deposition of compensatory lignin that is chemically distinct from Casparian strip lignin. We also report that a complete loss of endodermal lignification drastically impacts mineral nutrients homeostasis and plant growth.
Single-nucleus transcriptome analysis reveals cell type-specific molecular signatures across reward circuitry in the human brain
Authors: Tran Matthew N. , Maynard Kristen R. , Spangler Abby , Collado-Torres Leonardo , Sadashivaiah Vijay , Tippani Madhavi , Barry Brianna K. , Hancock Dana B. , Hicks Stephanie C. , Kleinman Joel E. , Hyde Thomas M. , Martinowich Keri , Jaffe Andrew E. 
Published: October 2020

AbstractSingle cell/nucleus technologies are powerful tools to study cell type-specific expression in the human brain, but most large-scale efforts have focused on characterizing cortical brain regions and their constituent cell types. However, additional brain regions - particularly those embedded in basal ganglia and limbic circuits - play important roles in neuropsychiatric disorders and addiction, suggesting a critical need to better understand their molecular characteristics. We therefore created a single-nucleus RNA-sequencing (snRNA-seq) resource across five human brain regions (hippocampus, HPC; dorsolateral prefrontal cortex, DLPFC; subgenual anterior cingulate cortex, sACC; nucleus accumbens, NAc; and amygdala, AMY), with emphasis on the NAc and AMY, given their involvement in reward signaling and emotional processing. We identified distinct and potentially novel neuronal subpopulations, which we validated by smFISH for various subclasses of NAc interneurons and medium spiny neurons (MSNs). We additionally benchmarked these datasets against published datasets for corresponding regions in rodent models to define cross-species convergence and divergence across analogous cell subclasses. We characterized the transcriptomic architecture of regionally-defined neuronal subpopulations, which revealed strong patterns of similarities in specific neuronal subclasses across the five profiled regions. Finally, we measured genetic associations between risk for psychiatric disease and substance use behaviors with each of the regionally-defined cell types. This analysis further supported NAc and AMY involvement in risk for psychiatric illness by implicating specific neuronal subpopulations, and highlighted potential involvement of an MSN population associated with stress signaling in genetic risk for substance use.
Haploid, diploid, and pooled exome capture recapitulate features of biology and paralogy in two non-model tree species
Authors: Lind Brandon , Lu Mengmeng , Vidakovic Dragana Obreht , Singh Pooja , Booker Tom , Yeaman Sam , Aitken Sally 
Published: October 2020

AbstractDespite their suitability for studying evolution, many conifer species have large and repetitive giga-genomes (16-31Gbp) that create hurdles to producing high coverage SNP datasets that captures diversity from across the entirety of the genome. Due in part to multiple ancient whole genome duplication events, gene family expansion and subsequent evolution withinPinaceae, false diversity from the misalignment of paralog copies create further challenges in accurately and reproducibly inferring evolutionary history from sequence data. Here, we leverage the cost-saving benefits of pool-seq and exome-capture to discover SNPs in two conifer species, Douglas-fir (Pseudotsuga menziesiivar.menziesii(Mirb.) Franco,Pinaceae) and jack pine (Pinus banksianaLamb.,Pinaceae). We show, using minimal baseline filtering, that allele frequencies estimated from pooled individuals show a strong positive correlation with those estimated by sequencing the same population as individuals (r > 0.948), on par with such comparisons made in model organisms. Further, we highlight the use of haploid megagametophyte tissue in identifying sites that are likely due to misaligned paralogs. Together with additional minor filtering, we show that it is possible to remove many of the loci with large frequency estimate discrepancies between individual and pooled sequencing approaches, improving the correlation further (r > 0.973). Our work addresses bioinformatic challenges in non-model organisms with large and complex genomes, highlights the use of megagametophyte tissue for the identification of paralog sites when sequencing large numbers of populations, and suggests the combination of pool-seq and exome capture to be robust for further evolutionary hypothesis testing in these systems.
Genetic Analysis of Methyl Anthranilate, Mesifurane, Linalool and Other Flavor Compounds in Cultivated Strawberry (Fragaria×ananassa)
Authors: Barbey Christopher R. , Hogshead Maxwell H. , Harrison Benjamin , Schwartz Anne E. , Verma Sujeet , Oh Youngjae , Lee Seonghee , Folta Kevin M. , Whitaker Vance M. 
Published: October 2020

ABSTRACTThe cultivated strawberry (Fragaria×ananassa) is an economically important fruit crop that is intensively bred for improved sensory qualities. The diversity of fruit flavors and aromas in strawberry result mainly from the interactions of sugars, acids, and volatile organic compounds (VOCs) that are derived from diverse biochemical pathways influenced by the expression of many genes. This study integrates multi-omics analyses to identify QTL and candidate genes for multiple aroma compounds in a complex strawberry breeding population. Novel fruit volatile QTL were discovered for methyl anthranilate, methyl 2-hexenoate, methyl 2-methylbutyrate, mesifurane, and a shared QTL on Chr 3 was found for nine monoterpene and sesquiterpene compounds, including linalool, 3-carene, β-phellandrene, α-limonene, linalool oxide, nerolidol, α-caryophellene, α-farnesene, and β-farnesene. Fruit transcriptomes from a subset of sixty-four individuals were used to support candidate gene identification. For methyl esters including the grape-like methyl anthranilate, a novelANTHANILIC ACID METHYL TRANSFERASE–like gene was identified. Two mesifurane QTL correspond with the known biosynthesis geneO-METHYL TRANSFERASE 1and a novelFURANEOL GLUCOSYLTRANSFERASE. The shared terpene QTL contains multiple fruit-expressed terpenoid pathway-related genes includingNEROLIDOL SYNTHASE 1(FanNES1). The abundance of linalool and other monoterpenes is partially governed by a co-segregating expression-QTL (eQTL) forFanNES1transcript variation, and there is additional evidence for quantitative effects from other terpenoid-pathway genes in this narrow genomic region. These QTL present new opportunities in breeding for improved flavor in commercial strawberry.
Transcribed germline-limited coding sequences inOxytricha trifallax
Authors: Miller Richard V. , Neme Rafik , Clay Derek M. , Pathmanathan Jananan S. , Lu Michael W. , Yerlici V. Talya , Khurana Jaspreet S. , Landweber Laura F. 
Published: October 2020

AbstractThe germline-soma divide is a fundamental distinction in developmental biology, and different genes are expressed in germline and somatic cells throughout metazoan life cycles. Ciliates, a group of microbial eukaryotes, exhibit germline-somatic nuclear dimorphism within a single cell with two different genomes. The ciliateOxytricha trifallaxundergoes massive RNA-guided DNA elimination and genome rearrangement to produce a new somatic macronucleus (MAC) from a copy of the germline micronucleus (MIC). This process eliminates noncoding DNA sequences that interrupt genes and also deletes hundreds of germline-limited open reading frames (ORFs) that are transcribed during genome rearrangement. Here, we update the set of transcribed germline-limited ORFs (TGLOs) inO. trifallax. We show that TGLOs tend to be expressed during nuclear development and then are absent from the somatic MAC. We also demonstrate that exposure to synthetic RNA can reprogram TGLO retention in the somatic MAC and that TGLO retention leads to transcription outside the normal developmental program. These data suggest that TGLOs represent a group of developmentally regulated protein coding sequences whose gene expression is terminated by DNA elimination.
High contrast probe cleavage detection on porous silicon biosensors via quantum dot labeled DNA probes
Authors: Layouni Rabeb , Dubrovsky Michael , Bao Mengdi , Chung Haejun , Du Ke , Boriskina Svetlana V. , Weiss Sharon M. , Vermeulen Diedrik 
Published: October 2020

AbstractUsing porous silicon (PSi) interferometer sensors, we show the first experimental implementation of the high contrast probe cleavage detection (HCPCD) mechanism. HCPCD makes use of dramatic optical signal amplification caused by cleavage of high-contrast nanoparticle labels on probes instead of the capture of low-index biological molecules. An approximately 2 nm reflectance peak shift was detected after cleavage of DNA-quantum dot probes from the PSi surface via exposure to a 12.5 nM DNase enzyme solution for 2 hrs. This signal change is 20 times greater than the resolution of the spectrometer used for the interferometric measurements, and the interferometric measurements agree with the interferometric response predicted by simulations and fluorescence measurements. These proof of principle experiments show a clear path to real-time, highly sensitive and inexpensive point-of-care readout for a broad range of biological diagnostic assays that generate signal via nucleic acid cleavage.
Structural basis of the human Scribble-Vangl2 association in health and disease
Authors: How Jing Yuan , Stephens Rebecca K. , Lim Krystle Y.B. , Humbert Patrick O. , Kvansakul Marc 
Published: October 2020

AbstractScribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been attributed to a loss of interaction with the planar cell polarity regulator Vangl2. We show that the Scribble PDZ domains 1, 2 and 3 are able to interact with the C-terminal PDZ binding motif of Vangl2 and have now determined crystal structures of these Scribble PDZ domains bound to the Vangl2 peptide. Mapping of mammalian neural tube defect mutations reveal that mutations located distal to the canonical PDZ domain ligand binding groove can not only ablate binding to Vangl2 but also disrupt binding to multiple other signaling regulators. Our findings suggest that PDZ-associated neural tube defect mutations in Scribble may not simply act in a Vangl2 dependent manner but as broad-spectrum loss of function mutants by disrupting the global Scribble-mediated interaction network.
CRISPR/Cas9-mediated generation of biallelic G0 anemonefish (Amphiprion ocellaris) mutants
Authors: Mitchell Laurie J. , Tettamanti Valerio , Marshall Justin N. , Cheney Karen L. , Cortesi Fabio 
Published: October 2020

ABSTRACTGenomic manipulation is a useful approach for elucidating the molecular pathways underlying aspects of development, physiology, and behaviour. However, a lack of gene-editing tools appropriated for use in reef fishes has meant the genetic underpinnings for many of their unique traits remain to be investigated. One iconic group of reef fishes ideal for applying this technique are anemonefishes (Amphiprioninae) as they are widely studied for their symbiosis with anemones, sequential hermaphroditism, complex social hierarchies, skin pattern development, and vision, and are raised relatively easily in aquaria. In this study, we developed a gene-editing protocol for applying the CRISPR/Cas9 system in the false clown anemonefish,Amphiprion ocellaris. Microinjection of eggs at the one-cell stage was used to demonstrate the successful use of our CRISPR/Cas9 approach at two separate target sites: the rhodopsin-like 2B opsin encoding gene (RH2B) involved in vision, and Tyrosinase-producing gene (tyr) involved in the production of melanin. Analysis of the sequenced target gene regions inA. ocellarisembryos showed that uptake was as high as 50% of injected eggs. Further analysis of the subcloned mutant gene sequences revealed that our approach had a 75% to 100% efficiency in producing biallelic mutations in G0A. ocellarisembryos. Moreover, we clearly show a loss-of-function intyrmutant embryos which exhibited typical hypomelanistic phenotypes. This protocol is intended as a useful resource for future experimental studies that aim to elucidate gene function in anemonefishes and reef fishes in general.